The use of reflectance confocal microscopy for the monitoring of Demodex density and degree of inflammation in rosacea patients using topical Ivermectin 1% (Soolantra)

Rosacea is a common inflammatory skin disease with a wide spectrum of clinical
features including erythema, teleangiectasia, edema, papules and pustules,
hypertrophy, and/ or ocular features. Common triggers for rosacea are e.g. sun
exposure, spicy food and alcohol consumption. The pathogenesis of rosacea is
unknown, although it is generally considered to be related to factors such as
abnormality in innate immunity, inflammatory reactions to cutaneous
micro-organisms (e.g. Demodex mites), ultraviolet damage, and vascular
dysfunction. Demodex folliculorum and Demodex brevis mites reside in sebaceous
follicles. Since their discovery, the pathogenicity of these mites have been
under debate. Steadily increasing with age, there is up to a 100% colonization
rate of Demodex mites in adults. High densities of demodex mites have been
found in rosacea-affected skin, which is correlated with a generalized increase
in inflammation markers. In a meta-analysis of case control studies a
statistically significant association between Demodex infestation and rosacea
was found.
In a multicenter, prospective study assessing the relationship between Demodex
load, rosacea, and skin innate immune markers, a 6-fold increase in Demodex
density in rosacea versus age-matched controls was demonstrated. Demodex mites
can be found during histopathological examination of tissues from a punch
biopsy from patients with rosacea. Other histopathological features of rosacea
include, parakeratosis, acanthosis, hyperkeratosis, perivascular and
perifollicular infiltrations, follicular spongiosis, exocytosis of inflammatory
cells into the hairfollicles, vascular dilatation and solar elastosis.

Reflectance confocale microscopy (RCM) is a non-invasive technique for in vivo
imaging of the skin that uses a near-infrared laser beam of 830nm. This
technique produces horizontal (en face) images of the skin up to approximately
200-250 micrometers in depth with a resolution comparable to conventional
histology. Currently, it is used for diagnosing melanoma skin cancer,
nonmelanoma skin cancer, inflammatory skin diseases and the detection of
infestation with fungi or parasites (e.g. scabies, Demodex mites). With the
RCM, Demodex mites are visualized as roundish or cone-shaped structures with a
bright contour, which are easily recognizable. Non-experienced RCM users can
therefore easily learn how to detect Demodex mites. Other established
diagnostic tests for the detection and quantification of Demodex mites include
standardized superficial skin biopsy, skin scraping, direct microscopic
evaluation of fresh secretions from sebaceous glands, and histopathological
evaluation of tissue from a punch biopsy. All these methods lead to alteration
of examined skin and can cause possible skin irritation, inflammation and
bleeding. RCM, on the other hand, allows non-invasive, in vivo visualization of
the upper layers of the skin at almost histological resolution without
alterations of the examined site. RCM also has the advantage, over the punch
biopsy, that it can monitor the same location over time. Furthermore, Erdermir
et al. concluded that RCM was superior to a standardized surface skin biopsy
for Demodex mite detection and quantification. In the study of Sattler et al.,
Harmelin et al., and Erdemir et al. the value of RCM for the detection and
quantification of Demodex folliculorum in patients with rosacea was shown.
Patients with rosacea had significantly higher numbers of mites in the skin
compared to healthy controls.

Just recently, topical Ivermectine (Soolantra®) has been introduced in the
treatment of rosacea. This cream has anti-parasitic and anti-inflammatory
properties resulting in the reduction of rosacea manifestations. Van Zuuren, et
al. showed in their Cochrane systematic review that topical Ivermectin was more
effective than placebo and Metronidazole cream in the treatment of rosacea. The
exact mechanism of action of topical Ivermectine is unknown, but it is
hypothesized that its anti-parasitic activity might play a role in the
reduction of Demodex population, contributing in positive treatment effects.
Because the amount of Demodex mites and some features of inflammation are not
visible to the naked eye, this study aims to monitor the in vivo changes in the
skin of rosacea patients using Ivermectin 1% (Soolantra®) cream with the RCM
during a treatment period of 16 weeks, with a follow up of 12 weeks after
ending the treatment.

Primary Objective:
To determine the monitoring and quantificational use of RCM in patients with
rosacea using topical Ivermectin.

Secondary Objective(s):
1. To correlate the in vivo skin changes, identified by RCM, to the clinical
assessment.
2. To determine prognostic RCM features that correlate to a successful clinical
response to topical Ivermectin in patients with rosacea.

Design: Prospective, observational, investigator-initiated, post marketing
study.

Patients are able to chose which rosacea treatment they prefer and in case they
chose for topical Ivermectin, they will be asked to participate in this study.
If necessary, a washout-period of topical and systemic rosacea treatments will
take place (in order to evaluate the treatment effect of topical Ivermectine
more accurately). They will be monitored using RCM-imaging, which is
non-invasive, safe and painless. More information on the pathogenesis of
rosacea and the mechanism of action of topical Ivermectin can be gained in this
way. The RCM-imaging and skin assessment (all non-invasive) may ask some time.