Personalized treatment of methotrexate in Crohn*s disease through therapeutic drug monitoring and prediction of clinical outcome: a known drug revisited

Crohn*s disease (CD) is a chronic autoimmune disease of the bowel affecting
40.000 individuals in the Netherlands. CD patients are commonly treated with
thiopurines such as azathioprine, while methotrexate (MTX), another equally
effective drug with a better safety profile, is underutilized. The objective of
this research is to employ MTX treatment in CD in a personalized fashion so
that all CD patients receive the most appropriate therapy. Currently,
therapeutic drug monitoring (TDM) is not possible because no stable plasma MTX
levels are reached. This may lead to undertreatment and non-response or
over-treatment and toxicity. To increase its efficacy and reduce toxicity,
individualized MTX dosing based on TDM is needed. We have developed a new assay
in red blood cells where MTX accumulates as the metabolite MTX poylglutamate
(MTX-PG). We know from studies with reumatoid arthritis patients using MTX that
higher MTX-PG levels correlates with good clinical response at three months
therapy. There was interindividual variety between RA patients using the same
dose MTX, which suggests that measurements of intracellular MTX-PG may be a
valuable TDM tool for clinician to individualize MTX treatment in an early
phase of treatment, in order to achieve faster disease remission and less
(end-organ) damage.
In CD patients not much is known about the pharmacokinetics and
pharmacodynamics of MTX. In this study we will obtain this relevant information
to make TDM possible in the near future.

To personalize MTX treatment in CD through a) therapeutic drug monitoring (TDM)
of MTX and b) prediction of MTX efficacy. We will develop TDM by measuring MTX
concentrations [MTX-polyglutamate concentration in erythrocytes] and
determining their association with clinical efficacy in order to establish a
cut-off concentration which discriminates between MTX responders and
non-responders. TDM will allow clinicians to determine whether a higher MTX
dose or escalation to a different therapy (i.e. biologicals) is necessary to
achieve clinical response. We will identify determinants crucial for MTX
pharmacokinetics and hence MTX-PG accumulation. We will also develop a
prediction model for MTX efficacy before MTX start in order to facilitate
clinicians to determine whether MTX is the optimal treatment or additional
agents should be implemented (i.e. biologicals).
Secondary objectives includes (a), association of MTX-PG with MTX toxicity (in
particular gastrointestinal intolerance with validation of MISS-questionnaire
in adult CD patients) and (b) determination of MTX-PG in different cells/tissue
(erythrocytes versus peripheral blood mononuclear cells (PBMCs) versus colonic
mucosa)

Observational.
A multi-center prospective longitudinal study with a follow-up of 12 months.

Only those patients for whom the treating physician already wanted to start MTX
treatment will be included. MTX is used as in usual clinical care. The effort
we ask of participants is filling in questionnaires and collecting extra blood
tubes at those moments where blood already would be drawn. We ask to collect
faeces for calprotectin, a marker already often used in routine clinical care.
This contains no risk, it only costs some time. Besides that, we give
participating patients an opportunity to give additional informed consent for
an additional rectoscopy and additional biopsies during clinical colonoscopy.
The risk of a biopsy during colonoscopy is low (1:10,000) and consist of
bleeding and bowel perforation. There is no direct benefit for the participants
during the study. However, with the data which we will retrieve from this study
we could enable the use of MTX-PG as a TDM tool in CD patients. Optimized and
individualized MTX treatment could improve care of CD patients by reducing the
incidence of flares and/or use of costly biologicals.