Parasites and inflammation fuel rosacea

Increasing evidence suggests that demodex mites may play a role in the pathogenesis of rosacea, a common, chronic inflammatory skin condition, according to the medical director of the Skin Centre for Dermatology in Peterborough, Ontario, Canada.

Read: Treat rosacea by treating the cause: demodex

Speaking here to fellow Canadian dermatologists at Dermatology Update (Ontario, 2015), Melinda Gooderham M.D., M.Sc., F.R.C.P.C., discussed how demodex mites are in greater abundance on the skin of patients with rosacea compared to individuals without rosacea.

"If not demodex, what causes rosacea?" Dr. Gooderham says. "What are the triggers that are causing this inflammatory cascade?"

Dr. Gooderham explains that, in an intact innate immune system, activation of the toll-like receptors incites a cleavage of pro-cathelicidin into cathelicidin, noting cathelicidin possesses properties needed for an effective immune system.

All individuals have demodex mites on their face, Dr. Gooderham notes, but a dysregulated immune response is believed to lead to rosacea.

Also read: Rosacea treatment shifts focus

It was observed in research that patients with rosacea have elevated expression of toll-like receptor 2 (TLR2) compared to patients with normal skin. Moreover, overexpression of TLR2 on keratinocytes, treatment with ligands of TLR2, and analysis of mice deficient in TLR2 led to a calcium-dependent discharge of kallikrein 5, a protease involved in the pathophysiology of rosacea, from keratinocytes. Kallikrein 5 that is elevated leads to the production of the LL-37 peptide (cathelicidin).¹

Cathelicidin peptide isoforms in rosacea are more plentiful than in normal skin and they also are of different molecular weights and promote angiogenesis. "There are variant forms of cathelicidin that are pro-inflammatory," explains Dr. Gooderham.

Demodex can also lead to disruption of the skin barrier, which can activate TLR2, according to Dr. Gooderham.

NEXT: Two types of demodex

Two types of demodex

There are two types of demodex in humans, and some investigations have sought to quantify the colonization of demodex folliculorum, which lives in sebaceous follicles, in patients with rosacea and how colonization is related to immune activation of the skin. Not only did skin sample analysis demonstrate that density of demodex folliculorum was 5.7 times greater in rosacea patients compared to control subjects, but there was a higher expression of genes carrying pro-inflammatory cytokines in rosacea, particularly in papulopustular rosacea compared to erythematotelangiectatic rosacea.²

Still, demodex density is increased in rosacea patients, independent of the rosacea subtype.

"There are patients with erythematotelangiectatic rosacea who have higher levels of demodex on the face and patients with papulopustular rosacea who have less (demodex on the face)," Dr. Gooderham says.

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Genes matter

Certain individuals are more genetically predisposed to develop rosacea. A recent analysis of twins aimed to separate environmental factors from genetic susceptibility in terms of the contribution to rosacea. Investigators concluded roughly half of the contribution to the rosacea score, as determined by the National Rosacea Society, is owing to genetics.³

Some investigators have speculated that a dysregulated immune response likely makes individuals more at risk of reacting to environmental stimuli like ultraviolet exposure and hot beverages.

Read: Rosacea's surprising genetic link

An emerging tool to measure the density of demodex mites in patients with rosacea is reflectance confocal microscopy. The technology can be used to detect and measure the mites in vivo in a non-invasive manner before and after treatment to measure any change in density. A decrease in density would be suggestive of clinical improvement.⁴

Greater understanding of the pathogenesis of rosacea may offer an explanation with respect to the efficacy of newer therapies such as ivermectin 1% cream, Dr. Gooderham says.

"Ivermectin is anti-parasitic and it has anti-inflammatory properties as well," says Dr. Gooderham. "It works at the level of cathelicidins. This may be why ivermectin is working (to treat rosacea)."

Research from two randomized, double-blind, controlled studies point to the effectiveness and safety of ivermectin in reducing inflammatory lesions when pitted against vehicle.⁵

In addition, the therapy has been shown to be safe and effective in extension studies, supporting its use as a long-term treatment.⁶

Disclosure: Dr. Gooderham has been a speaker and investigator for Galderma.

References:

Yamasaki K, Kanada K, Macleod DT,  et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes.  J Invest Dermatol. 2011;131(3):688-97.

Casas C, Paul C, Lahfa M, et al. Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Exp Dermatol. 2012;21(12):906-10.

Aldrich N, Gerstenblith M, Fu P, et al. Genetic vs. Environmental Factors that Correlate with Rosacea: A Cohort-Based Survey of Twins. JAMA         Dermatol. 2015 Aug 26.

Bahadoran P. Br J Dermatol. 2015;173(1):8-9.

Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014; 13(3):316-23.

Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs. azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials. J Drugs Dermatol. 2014;13(11):1380-6.