Topical Ivermectin Study Sheds Light on Dysbiosis in Rosacea

Topical ivermectin has significant clinical efficacy and decreases the density of Demodex mites found in the skin of people with rosacea, but cutaneous dysbiosis remains, according to a report presented at the recent European Academy of Dermatology and Venereology (EADV) 2023 Congress.

"This is the first hint that the host's cutaneous microbiome plays a secondary role in the immunopathogenesis of rosacea," said Bernard Homey, MD, director of the Department of Dermatology at University Hospital Düsseldorf in Germany.

"In rosacea, we are well aware of trigger factors such as stress, UV light, heat, cold, food, and alcohol," he said. "We are also well aware that there is an increase in Demodex mites in the pilosebaceous unit."

Research over the past decade has also started to look at the potential role of the skin microbiome in the disease process, but answers have remained "largely elusive," Homey said.

Ivermectin Helps, but How?

Ivermectin 1% cream (Soolantra) has been approved by the US Food and Drug Administration since 2014 for the treatment of the inflammatory lesions that are characteristic of rosacea, but its mechanism of action is not clear.

Homey presented the results of a study of 61 patients designed to look at how ivermectin might be working in the treatment of people with rosacea and investigate if there was any relation to the skin microbiome and transcriptome of patients.

The trial included 41 individuals with papulopustular rosacea and 20 individuals who did not have rosacea. For all patients, surface skin biopsies were performed twice 30 days apart using cyanoacrylate glue; patients with rosacea were treated with topical ivermectin 1% between biopsies. Skin samples obtained at day 0 and day 30 were examined under the microscope, and Demodex counts (mites/cm²) of skin and RNA sequencing of the cutaneous microbiome were undertaken.

The mean age of the patients with rosacea was 54.9 years, and the mean Demodex counts before and after treatment were a respective 7.2 cm² and 0.9 cm².

Using the Investigator's General Assessment to assess the severity of rosacea, Homey reported that 43.9% of patients with rosacea had a decrease in scores at day 30, indicating improvement.

In addition, topical ivermectin resulted in a marked or total decrease in Demodex mite density for 87.5% of patients (n = 24) who were identified as having the mites.

Skin Microbiome Changes Seen

As a form of quality control, skin microbiome changes among the patients were compared with control patients using 16S rRNA sequencing.

"The taxa we find within the cutaneous niche of inflammatory lesions of rosacea patients are significantly different from healthy volunteers," Homey said.

Cutibacterium species are predominant in healthy control persons but are not present when there is inflammation in patients with rosacea. Instead, Staphylococcus spp "take over the niche, similar to atopic dermatitis," he noted.

Looking at how treatment with ivermectin influences the organisms, the decrease in C acnes seen in patients with rosacea persisted despite treatment, and the abundance of S epidermidis, S hominis, and S capitis increased further. This suggests a possible protective or homeostatic role of C acnes but a pathogenic role for Staphylococci, explained Homey.

"Surprisingly, although inflammatory lesions decrease, patients get better, the cutaneous microbiome does not revert to homeostatic conditions during topical ivermectin treatment," he observed.

There is, of course, variability among individuals.

Homey also reported that Snodgrassella alvi ― a microorganism believed to reside in the gut of Demodex folliculorum mites ― was found in the skin microbiome of patients with rosacea before but not after ivermectin treatment. This may mean that this microorganism could be partially triggering inflammation in rosacea patients.

Looking at the transcriptome of patients, Homey said that there was downregulation of distinct genes that might make for more favorable conditions for Demodex mites.

Moreover, insufficient upregulation of interleukin-17 pathways might be working together with barrier defects in the skin and metabolic changes to "pave the way" for colonization by S epidermidis.

Pulling It Together

Homey and associates conclude in their abstract that the findings "support that rosacea lesions are associated with dysbiosis."

Although treatment with ivermectin did not normalize the skin's microbiome, it was associated with a decrease in Demodex mite density and the reduction of microbes associated with Demodex.

Margarida Gonçalo, MD, PhD, professor of dermatology at the University of Coimbra in Portugal, who co-chaired the late-breaking news session where the data were presented, asked whether healthy and affected skin in patients with rosacea had been compared, rather than comparing the skin of rosacea lesions with healthy control samples.

"No, we did not this, as this is methodologically a little bit more difficult," Homey responded.

Also co-chairing the session was Michel Gilliet, MD, chair of the Department of Dermatology at the University Hospital CHUV in Lausanne, Switzerland. He commented that these "data suggest that there's an intimate link between Demodex and the skin microbiota and dysbiosis in in rosacea."

Gilliet added: "You have a whole dysbiosis going on in rosacea, which is probably only dependent on these bacteria."

It would be "very interesting," as a "proof-of-concept" study, to look at whether depleting Demodex would also delete S alvi, he suggested.

The study was funded by Galderma. Homey has acted as a consultant, speaker or investigator for many pharmaceutical companies including Galderma.

European Academy of Dermatology and Venereology (EADV) 2023 Congress: Abstract 6559. Presented October 12, 2023.

Sara Freeman is a medical journalist based in London, England.