Investigation of flare and remission in atopic dermatitis in an integrated longitudinal study: effects of systemic treatment with cyclosporine A

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disease
with an estimated prevalence of around 10% of the adult population. AD is
characterized by exacerbations (flares) of increased disease severity and
periods of more stable chronic disease or absence of clinical signs/symptoms
(remission). There is currently no broadly accepted definition of an AD flare,
although the need for treatment escalation is commonly used as a surrogate
measure. Identification of molecular markers of flare and remission in atopic
dermatitis would represent a significant advance in disease understanding.

Recent technical and scientific advances have enabled detailed analyses of
molecular signatures of disease in a wide variety of tissues. For example,
analysis of gene expression in skin biopsies has revealed important information
regarding molecular pathways responsible for driving disease pathology in a
wide variety of inflammatory skin conditions, including atopic dermatitis.
Analysis of protein biomarkers in serum has further extended our knowledge of
biomarkers of atopic dermatitis. Finally, it is increasingly apparent that the
skin and gut microbiome are critical players in the pathology of skin diseases,
including atopic dermatitis.

What has so far been underexplored in the study of molecular signatures in
atopic dermatitis is a wide systems biology approach, in which multiple
analysis techniques (a so-called multi-omics approach) are applied in a
clinical setting. Here we propose using a systems biology approach to explore
flare and remission in subjects with AD treated with Cyclosporine A (CsA).
Cyclosporine A is a registered therapy for moderate-to-severe AD in the
Netherlands, and rapid resolution is expected to occur in most subjects.

What has so far been underexplored in the study of molecular signatures in
atopic dermatitis is a wide systems biology approach, in which multiple
analysis techniques (a so-called multi-omics approach) are applied in a
clinical setting where patients are effectively treated and go from flare to
remission.

Here we propose to use a systems biology approach to explore flare and
remission in subjects with AD treated with Cyclosporine A (CsA). Cyclosporine A
is a registered therapy for moderate-to-severe AD in the Netherlands, and rapid
resolution is expected to occur in most subjects.

The study is a single-center, observational study, with a four-week follow-up
period. 40 subjects with moderate-to-severe AD will be enrolled.

Subjects with an AD flare that are candidates for CsA treatment will be
included in the study. Patients with a (EASI score * 10 at screening and *16 at
the baseline visit). After a 1-week screening period, allowing for wash-out of
topical corticosteroids (TCS) and systemic treatments, subjects will receive a
4-week course of high-dose CsA (4-5 mg/kg/day).

Clinical parameters will be evaluated at baseline, two weeks after initiation
of treatment, and four weeks after initiation of treatment according to the
regular follow up schedule.

Blood samples for explorative biomarker analyses will be taken at baseline,
after 2 and 4 weeks of CsA treatment.
Skin biopsies will be taken at baseline (flare) and after 4 weeks of CsA
treatment (remission).

Risks:
Cyclosporin A is registered for the treatment of atopic dermatitis. Therefore
patients are not exposed to additional risks compared to patients treated
regularly with cyclosporin A.
However, trial patients are exposed to a one-week lasting wash-out period (if
they have used topical steroids over the last weeks, which is often not the
case) in which they are asked not to use any topical corticosteroid treatment
nor a systemic AD treatment. This might lead to a temporary increase in
severity of their AD.


Burden:
Subjects will be asked for 2 sets of (lesional and nonlesional) skin biopsies.
Performing a biopsy entails a slight risk of haemorrhage and infection. A small
scar at the site of biopsy will gradually fade in colour.

Patients will be asked to donate some additional blood (during regular safety
lab blood checks).