Research into the microbiome of the skin is advancing. A greater understanding of how the different microbes interact may lead to new treatment options for conditions like rosacea, but more questions still remain.
Researchers are learning more about the pathophysiology of rosacea, including the many ways in which the human microbiome might affect the skin. Studies uncovering potential roles of Demodex mites and more in rosacea could result in new options for treatment, but big questions remain.
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“We understand that this is an inflammatory disease and involves abnormalities in the immune system,” says Linda Stein Gold, M.D., director of dermatology clinical research at Henry Ford Hospital, Detroit, Mich.
Demodex mites normally exist in the human microbiome but the numbers of these mites appear to be more than four-fold on rosacea sufferers’ facial skin, according to Frank Powell, M.D., consultant dermatologist at Mater Misericordiae Hospital in Dublin and former president of the European Academy of Dermatology and Venereology. Dr. Powell was among the roundtable experts on the clinical implications of Demodex in rosacea during the American Academy of Dermatology’s March 2015 annual meeting in San Francisco.
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“Researchers have more recently discovered that while Demodex folliculorum and D. brevis live in the hair follicles and sebaceous glands of the facial skin, D. folliculorum is also found in the meibomian glands of ocular rosacea patients,” Dr. Powell said in a July 30, 2015 National Rosacea Society press release. “In the mites’ brief life span of 14 days, they live and reproduce in the pilosebaceous units, subsisting on sebum and cellular contents, and emerge from the follicles primarily at night.”
But how this all plays out for individual rosacea patients remains unclear.
Diane Thiboutot, M.D., professor of dermatology and vice-chair for Research at Penn State University, was on that AAD roundtable and says there are two things that have emerged in the literature when it comes to rosacea and Demodex.
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“There’s a lot of evidence to demonstrate that patients with rosacea have more Demodex mites compared to patients without rosacea. But just the presence of Demodex, in and of itself, doesn’t induce rosacea. There seems to be a quantitative difference among Demodex mites in people with rosacea,” Dr. Thiboutot says.
Another important finding is the Demodex mites’ involvement with toll-like receptor-2 (TLR-2).
“There are studies to show that the Demodex mite is able to induce inflammation by activating the TLR-2,” Dt. Thiboutot says.
There’s a long way to go, however, before these findings translate to treatment. For example, TLR-2 activation is needed to fight off pathogens, so stopping it entirely isn’t an option.
“We need more studies looking at a cause and effect between the presence of Demodex and the development of rosacea, which can be challenging because, although rosacea is common, we really don’t have a clear idea of the exact steps involved in its pathogenesis,” Dr. Thiboutot says.
And while researchers are detecting the presence and quantity of Demodex by performing follicular biopsies, it might be too early for practicing dermatologists to think about testing for Demodex in their rosacea patients, according to Dr. Thiboutot.
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“I think that until there’s more information on Demodex, I don’t feel that follicular biopsies are necessary at the moment,” Dr. Thiboutot says.
Other microorganisms associated with rosacea include staph epidermidis, as well as a bacteria that lives on Demodex mites, called Bacillus oleronius.
“Bacillus oleronius may have a role in stimulating the immune system. All [the microorganisms] work by stimulating the TLR-2,” says Dr. Stein Gold, who was also a member of the AAD panel.
Another interesting direction into looking at what causes rosacea is in the study of mast cells.
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“If you biopsy patients with rosacea, they seem to have more mast cells in their dermis,” Dr. Stein Gold says.
“There’s an interesting animal study that was done. If you take mice and inject the abnormal proinflammatory peptides that are found in rosacea, you can reproduce the signs and symptoms of rosacea. If you took those same mice and they don’t have any mast cells, that doesn’t happen. So, it does appear that mast cells have an important role, which might be an avenue of treatment down the line.”1
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One treatment that is clinically effective in studies is topical ivermectin, an FDA approved for rosacea treatment and an antiparasitic drug.
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“We know that [ivermectin] has some activity against Demodex. It’s used commonly in veterinary medicine to treat Demodex,” Dr. Stein Gold says. “But it hasn’t been studied extensively in humans. And we haven’t really evaluated to a real scientific degree the effect of Demodex on different treatment modalities.”
Ivermectin also has anti-inflammatory properties, which affect cellular and the humoral immune responses and has been shown to downregulate some proinflammatory cytokines, according to Dr. Stein Gold.
“Some people have treated Demodex by using oral ivermectin. But I haven’t really seen any good clinical trials that have evaluated that. It’s more case reports that people talk about,” Dr. Stein Gold says.
On the horizon is oxymetazoline2, which is in clinical trials and, like topical brimonidine, targets rosacea’s erythema.
If these are potential “in” treatments for rosacea, one that’s out is using a full-strength oral doxycycline at high doses for prolonged periods to treat the skin disease. High doses are unnecessary, according to Dr. Stein Gold.
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“We know that the role of doxycycline in rosacea is really used for anti-inflammatory properties and, that, by using anti-inflammatory doses instead of using high dose doxycycline, we actually are able to control rosacea very well. By keeping those low doses, we don’t have to worry about the development of resistance,” Dr. Stein Gold says.
Low dose oral doxycycline is the answer, according to Dr. Thiboutot.
“We know more about doxycycline because doxycycline has been shown to affect matrix metalloproteinases (MMPs) enzymes that may play a role in rosacea with regard to cathelicidin activation,” Dr. Thiboutot says. “So, the treatments are: low-dose oral doxycycline, topical metronidazole, topical azelaic acid and topical ivermectin.”
Dr. Stein Gold recommends that dermatologists use combination approaches in the treatment of rosacea, based on individual patient’s needs.
First, it’s important to get the inflammatory lesions under control rapidly, according to Dr. Stein Gold.
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“Topical ivermectin can be quite effective for that, and was studied in patients with moderate to severe rosacea. We have a new azelaic acid foam that was recently approved that may be better tolerated than some of the other vehicles,” Dr. Stein Gold says.
Next, tackle other bothersome aspects of rosacea, including erythema.
“For that, you can use topical brimonidine or, possibly, oxymetazoline in the future,” she says. “Then, you can combine other modalities like laser therapy to treat the background blood vessels.”
Rosacea research looking at the microbiome of the skin-presence of bacteria, viruses, fungi and mites-is advancing.
“How all these different microbial concerns interact with each other, that’s a very interesting question. We’re just sort of touching the tip of the iceberg when it comes to knowing about what the interactions are between the various microbiota on the skin,” Dr. Thiboutot says.
Dr. Stein Gold is a consultant for Galderma, Bayer and Allergan.
Diane Thiboutot, M.D., is a consultant to Galderma and Allergan.
Muto Y, Wang Z, Vanderberghe M, Two A, Gallo RL, Di Nardo A. J Invest Dermatol. 2014 Nov;134(11):2728-36.
Generali JA, Cada DJ. Oxymetazoline (topical): rosacea. Hosp Pharm. 2013;48(7):558-9.