Research sheds light on pathophysiology of acne, rosacea

Although the symptoms of acne and rosacea are well established, clear and definitive etiologies of these conditions have largely been unknown. Recent research, however, has shed new light into the pathophysiology of these conditions, paving the way for more targeted therapies.

For rosacea, all of the agents currently approved by the Food and Drug Administration (topical metronidazole, azelaic acid 15 percent gel, doxycycline 40 mg modified-release capsule once daily [subantimicrobial dose]) and most studies with non-approved agents (oral antibiotics, topical calcineurin inhibitors) have been completed in patients with papulopustular rosacea.

“More recent basic science research has shown that rosacea is an inflammatory skin disorder, with neurovascular dysregulation and augmented immune detection and response identified as the two major pathophysiologic components of rosacea,” says James Q. Del Rosso, D.O., clinical professor (dermatology adjunct faculty), Touro University College of Osteopathic Medicine, and in private practice of dermatology at Las Vegas Skin and Cancer Clinics, Henderson, Nev.

Examining the cathelicidin pathway

The cathelicidin pathway, a cascade that is present normally in skin to recognize and neutralize invasion by microbial organisms, is upregulated and hyper-reactive in facial skin of rosacea patients, Dr. Del Rosso says. This upregulation produces excess cathelicidin (LL-37), which induces vasodilation of superficial facial vasculature, inflammation and vascular proliferation. The latter effect over time leads to persistent diffuse central facial redness both during and between flares as the dilated and enlarged vessels become fixed.

According to Dr. Del Rosso, it has been shown over the past few years that doxycycline inhibits matrix metalloproteinase enzymes (MMPs) that are involved early in the activation of the cathelicidin pathway. In addition, azelaic acid has been shown to inhibit the serine protease enzyme, which converts an inactive precursor protein (hCAP18) to active cathelicidin.

“It is interesting that both doxycycline and azelaic acid modulate the cathelicidin pathway at different steps which may explain the observation that the combination of the two agents appears to speed up and augment the therapeutic response as compared to monotherapy in patients with rosacea who have papulopustular lesions,” Dr. Del Rosso says.

Addressing facial erythema

Topical alpha-adrenergic agonists are becoming of particular interest for the medical management of persistent diffuse central facial erythema of rosacea, which is due to fixed proliferation and enlargement of superficial skin vasculature. These agents stimulate alpha-receptors in the smooth muscle layer of superficial skin vessels resulting in vasoconstriction, Dr. Del Rosso says, leading to reduced facial skin redness over a period of up to 12 hours after a single application.

Oxymetazoline (available in a nasal solution) has been shown to be effective for facial erythema in rosacea patients in a few case reports, he says; however, no studies have been published to date. It is currently under development for this use.

Most recently FDA-approved for treatment of persistent nontransient facial erythema of rosacea in patients age 18 and older, brimonindine tartrate 0.5 percent gel (brimonidine 0.33 percent, Mirvaso, Galderma) applied once daily has been shown to reduce diffuse facial erythema of rosacea with a usual onset within 30 minutes and with peak activity over approximately eight to 10 hours. According to Dr. Del Rosso, the safety profile appears to be favorable, rebound has not emerged as a major problem with this agent, and tachyphylaxis has not been observed.

“This therapy treats the vascular component of rosacea which is not addressed by the therapies which treat the inflammatory component with papulopustular lesions of the disease,” Dr. Del Rosso says.

According to Joshua Zeichner, M.D., one of the most difficult challenges in the treatment and management of rosacea is to undo the changes occurring in the skin, making prevention of progression of signs and symptoms a central part of an ideal treatment approach.

“Up until this point, all we have to treat the background redness of rosacea are laser and light treatments, which are effective,” he says. “However, once you treat the redness, it can recur because you are not changing the underlying skin pathophysiology. Now we have the opportunity to use both modalities, meaning laser and light therapies as well as some of these new topicals.

“The goal would be to undo some of the damage, and prevent it from recurring. However, more research needs to be done to see how these vasoconstriction medications change the progression of the disease.”

Pathophysiology of acne

Similar to rosacea, new data is emerging regarding the pathophysiology of acne, showing that inflammation of the skin precedes the development of the microcomedone.

It used to be thought that the microcomedone was the initiating lesion in acne, but according to Dr. Zeichner, who is director of cosmetic and clinical research, department of dermatology, Mount Sinai Medical Center, New York, that might not be the case.

“Interestingly, there is data showing that once the acne improves, there is still inflammation in the skin. Current research is looking at why the inflammation is present and differences in patients’ inflammatory responses,” Dr. Zeichner says.

New isotretinoin formulations have recently become available, he says, such as Zenatane (Promius Pharma), a branded generic bioequivalent formulation of isotretinoin.

The drug is prescribed through a specialty pharmacy that ships the medication to patients overnight via UPS, and assists them to stay on track in the iPLEDGE program. According to Dr. Zeichner, the advantage of using Zenatane is the concierge service that the pharmacy plays and provides, facilitating accessibility and adherence for patients. Absorica (Ranbaxy Laboratories) is another new formulation of isotretinoin that contains Lidose (SMB Laboratories) technology, which facilitates the delivery of the drug.

Isotretinoin is optimally absorbed in the presence of a fatty meal, Dr. Zeichner says, and since patients can be forgetful in when and how to take their medication, formulations that already include the fat component within the matrix of the pill itself can help optimize the absorption of the drug, even on an empty stomach.

“These new medications for acne and rosacea are a step in the right direction that ultimately help us better treat and manage these conditions,” Dr. Zeichner says. “I believe that the future will be brighter as we continue to gain a better understanding of the pathophysiology of these conditions, allowing us to develop more targeted treatments and therapeutic options for our patients.”

Disclosures: Dr. Del Rosso has served as a consultant, advisory board participant, clinical investigator, and speaker and is currently active in some or all of these roles for: Allergan, Bayer (Dermatology), Dermira, Ferndale, Galderma, Onset Dermatologics, Promius, Ranbaxy, Taro Pharmaceuticals, Unilever, Valeant, and Warner-Chilcott. He has provided limited professional services within the past three years as a consultant for Anacor, Dermira, Eisai and Primus. He has served as a consultant and speaker for Obagi Medical Products and Pharmaderm. He has also been a consultant and advisory board moderator for Quinnova and a consultant and advisory webcast moderator for TriaBeauty. Dr. Zeichner has served as a consultant for Promius Pharma and Ranbaxy Laboratories.