NEW YORK – Rosacea seems to represent a Möbius strip of an overly enthusiastic immune response, with chemicals that recruit neutrophils, which, in turn, activate even more immunomodulators.
Researchers have been pointing the finger at trigger-happy neutrophils for more than a decade, Dr. David E. Cohen said at the summer meeting of the American Academy of Dermatology. But this group of cells is really more of an accomplice than a mastermind.
M. Sand, et al/Head & face medicine/ISSN 1746-160X/CC BY 2.0
Inflammatory papules and pustules are observed over the nose in an individual with rosacea.
“Neutrophils were once the alpha and omega of rosacea,” said Dr. Cohen, the Charles C. and Dorothea E. Harris Professor of Dermatology, New York University. “But what are they doing on the skin and why are they there? They’re doing exactly what they’re supposed to do – defending against invasion by dumping out a whole poisonous soup of chemicals,” designed to protect and defend against microbes.
In the chronic disease of rosacea, however, these frontline soldiers are constantly recruited, even when there’s no invader to fight. They continue to carry out their preprogrammed attacks, releasing proteins that activate enzymes that stimulate immunomodulators that, in turn, call more neutrophils to the battlefield. Now, new research suggests that cathelicidins – antimicrobial peptides that are especially present in epithelial cells – are giving neutrophils their marching orders.
“Cathelicidins sit fully engaged on the skin and, the minute there’s a breach, they are turned on as the first defense,” Dr. Cohen said. “We need that kind of help right away – we can’t afford to wait around” for the second wave of defenders: neutrophils and lymphocytes.
This command seems to be bidirectional, though. Neutrophils release matrix metalloproteases (MMPs), enzymes critical for wound healing. MMPs remove dead extracellular matrix and microbes, prepare the wound bed for angiogenesis, and stimulate epidermal cell migration. But these benefits also exacerbate the things that make rosacea such a tough problem. By dissolving tissue, MMPs ramp up inflammation. By stimulating angiogenesis, they contribute to vasodilation, erythema, and telangiectasias.
And, Dr. Cohen noted, MMPs also just happen to recruit more neutrophils, which are capable of activating triptych enzymes, which turn on cathelicidins. “Now, a loop is being theorized,” he said. “The recruitment tools are kept on and this keeps cycling and cycling allowing the neutrophils to stay in the skin” for years.
The exaggerated presence of MMPs is likely the very reason that the tetracycline class of antibiotics can be so effective during rosacea exacerbations, Dr. Cohen said. The drugs aren’t necessarily fighting bacteria – instead, their anti-MMP properties function as a temporary break in this inflammatory loop. “They interfere with MMP, and you can’t turn on cathelicidin without MMP. If you lock MMP down, you can break the cycle because there is no neutrophil recruitment.”
Interestingly, he said, antibiotics that target MMP appear to suppress the enzymes at subantimicrobial doses. “This opens the possibility that we might be able to treat with these drugs and not exert antibiotic effects,” lessening the problems associated with indiscriminate antibiotic usage.
Inflammatory overdrive makes rosacea skin hypersensitive to any kind of inflammatory trigger, said Dr. Hilary Baldwin, medical director of the Acne Treatment and Research Center in Morristown, N.J. At the meeting, Dr. Baldwin discussed several new topical medications aimed at breaking the cycle:
• 1% Ivermectin: People with rosacea can harbor up to six times more demodex mites than can people without the disorder. The explanation behind this relationship is unclear: Is rosacea skin somehow more hospitable to the mite, or is an excess of mites a direct causative factor? Whatever the interaction, topical ivermectin breaks the link as both an antimicrobial and an anti-inflammatory agent. Ivermectin directly inhibits cellular and humoral immune response, and regulates tumor necrosis factor–alpha and interleukins 1-beta and 10.
Two randomized, double-blind vehicle-controlled studies evaluating 1% ivermectin cream in patients with papulopustular rosacea found that almost 80% of rosacea patients were clear or nearly clear on the Investigator’s Global Assessment (IGA) scale at 12 weeks – significantly more than those who were using a vehicle placebo. Inflammatory lesions significantly decreased and adverse events were similar to those associated with the vehicle (J Drugs Dermatol. 2014 Mar;13[3]:316-23). Another study found that ivermectin was significantly more effective than metronidazole, she said.
• Azelaic acid: A phase III study examined azelaic acid foam in almost 1,000 patients with moderate to severe papulopustular rosacea. IGA was clear or near-clear in 32% of the active group at 12 weeks, and 23.5% of the vehicle control group – a significant difference. There were significantly fewer inflammatory lesions among those in the active treatment group as well. Drug-related cutaneous adverse events were significantly more common among those treated with azelaic acid (7% vs. about 4%) and were mostly pain, pruritus, and dryness at application site (Cutis. 2015 Jul;96[1]:54-61).