Clues about rosacea pathogenesis spark treatment advances

National report - Therapies in the investigational drug pipeline are joining existing treatment options for redness associated with rosacea, according to two clinicians.

Findings from a Cochrane Systematic Review show evidence of the effectiveness of topical azelaic acid, topical metronidazole and oral subantimicrobial dose doxycycline for the treatment of papulopustular rosacea (PPR). The use of brimonidine 0.33 percent topical gel (Mirvaso, Galderma), laser and light modalities, and various off-label pharmacologic treatments also serve as effective options for managing the facial erythema, telangiectasias and phymatous changes associated with this common disease, says Hilary E. Baldwin, M.D.

The Food and Drug Administration (FDA) in August 2013 approved topical brimonidine gel for the treatment of facial redness in adults with rosacea. Although there was some evidence from clinical trials that facial redness improved in patients using topical azelaic acid gel or subantimicrobial dose oral doxycycline to treat PPR, the change in skin color was predominantly due to a reduction in perilesional erythema rather than in the background redness that is mediated by vasodilation as well as inflammation, says Dr. Baldwin, associate professor and vice chair, department of dermatology, State University of New York at Brooklyn.

brimonidine is an alpha-2 agonist that causes reversible vasoconstriction of the small blood vessels in the skin. When applied topically, redness is reduced within about 30 minutes, and the benefit persists for about 12 hours, after which there is a gradual return to the baseline state.

“Due to its temporary effect, I instruct patients to apply topical brimonidine in the morning on days when they care about reducing facial redness and to forego its use on the days when they are not concerned,” Dr. Baldwin says.

She notes that there is no “Cinderella phenomenon” with topical brimonidine use, wherein the medication effect wears off and the face suddenly becomes bright red again. In the pivotal clinical trials, topical brimonidine was not associated with rebound of facial erythema, i.e., worsening of erythema compared with baseline after treatment cessation.

Worse before it gets better

Since the product launched, there have been reports of patients who feel their face is slightly redder on the day after using topical brimonidine. Those cases appear, however, to be uncommon with a rate of about 5 to 10 percent.

“The redness in these patients is mild, short-lived and responds to repeated application of brimonidine,” Dr. Baldwin says.

There also are rare reports of worsening of erythema associated with stinging and burning, which may persist for a week or longer. The cause of this reaction is unknown.

“It is important to remind patients that this is a drug, not a cosmetic, and as such it may be associated with side effects such as worsening of erythema,” Dr. Baldwin says.

Another topical vasoconstrictor, oxymetazoline, is under investigation for the treatment of erythema associated with rosacea, and positive results were reported from phase 1 and 2 trials.

Subantimicrobial dose doxycycline (Oracea 40 mg, Galderma) is the only FDA-approved oral medication for the treatment of inflammatory lesions of rosacea. The approval dates back to 2006; a year later, published results of a randomized, double-blinded study reported by Joseph Fowler Jr., M.D., showed that the combination of subantimicrobial dose doxycycline with topical metronidazole 1 percent gel led to faster and significantly greater reductions in papulopustular lesion counts than treatment with topical metronidazole alone.

The findings of this study resulted in a paradigm shift in rosacea management that favors introducing anti-inflammatory dose doxycycline earlier in the treatment algorithm, Dr. Baldwin says.

Time of the essence

“We know that rosacea can have a significant deleterious psychosocial impact on affected patients. Therefore, speed is of the essence when it comes to treatment efficacy,” she says.

Dr. Baldwin is also emphatic in pointing out that dermatologists should think twice before prescribing standard antimicrobial doses of doxycycline or other tetracyclines to treat rosacea.

“It seems that not all clinicians are getting the message that antibiotic resistance is a crucial issue and that they have a responsibility for practicing good antibiotic stewardship. All evidence points towards rosacea being an inflammatory disease, not an infectious condition. We currently have many good non-antibiotic choices for its treatment, and it is my opinion that use of full dose antibiotics is not good patient management except for a last resort.”

In the area of off-label treatments, Dr. Baldwin notes that there is evidence from research conducted many years ago by Albert Kligman, MD, showing that low-dose oral isotretinoin improves nearly all aspects of rosacea and can even reduce rhinophyma size and formation. While the benefits of isotretinoin treatment for rosacea are not durable after the medication is stopped, disease control can be maintained using an extremely low dose of isotretinoin.

Dr. Baldwin says that she considers long term isotretinoin to treat recalcitrant rosacea in men and women of non- childbearing potential. She usually initiates therapy with 20 mg daily and decreases the dose after improvement is achieved while monitoring for recurrence. Most patients can be maintained on 10 mg daily or every other day.

New directions

Looking ahead, there are promising agents in the investigational drug pipeline, and findings from research on the pathogenesis of rosacea are suggesting targets for developing novel therapies, according to Diane Thiboutot, M.D.

Basic science and clinical research spearheaded by Richard Gallo, M.D., has focused interest on the roles of cathelicidin and kallikrein 5 (Klk5) in the pathophysiology of rosacea. The cathelicidins are natural antimicrobial peptides, but in rosacea patients they may be abnormally processed to forms with pro-inflammatory activity as a result of elevated levels of Klk5.

This information suggests strategies for developing targeted therapies for rosacea. For example, use of a protease inhibitor interfering with the activity of Klk5 has shown promise as a treatment for rosacea, says Dr. Thiboutot, professor and vice chair for research, department of dermatology, Penn State Hershey Dermatology, Hershey, Pa.

The information about cathelicidin and Klk5 has also led to studies investigating whether the benefits of existing treatments for rosacea might be mediated by their ability to affect these elements of the innate immune system. Interestingly, research by Dr. Gallo and colleagues showed that azelaic acid inhibits Klk5 and its gene expression in cultured keratinocytes. In addition, they reported that doxycycline indirectly inhibits Klk5 activity and therefore cathelicidin production. The effect on Klk5 appears to be mediated through inhibition of matrix metalloproteinases.

Although a role of Demodex in the development of rosacea remains unproven, the finding by some investigators that the density of Demodex mites is increased in the skin of rosacea patients and hypotheses about their relevance in rosacea pathogenesis has stimulated interest in acaricidal agents. The most rigorously studied treatment within this category is topical ivermectin 1 percent cream, which has advanced into phase 3 studies where it is being comparing against azelaic acid gel and metronidazole cream for the treatment of PPR.

“Data from earlier research with ivermectin showed it was more effective than placebo in treating PPR. However, whether any benefit of ivermectin is due to activity against Demodex and/or involves some anti-inflammatory effect is unclear,” Dr. Thiboutot says. “Part of the challenge in determining its mechanism of action is that we have still not put together all of the pieces in solving the puzzle of the pathogenesis of rosacea. Cathelicidin may be one part of the story, but multiple other factors, including Demodex, may be contributing either alone or through more complex interactions.”

Dr. Thiboutot notes that as researchers learn more about the pathogenesis of the condition, they can better understand the benefits of certain medications.

“At the same time, expanding information about the mechanisms of medications can improve our knowledge about rosacea pathogenesis and the opportunities for targeted therapies,” she says.

Disclosures: Dr. Thiboutot has served as an investigator or consultant for Bayer and Galderma. Dr. Baldwin serves as a consultant, adviser and/or on the speakers’ bureau for Galderma, Allergan, Valeant, Anacor, Aqua, L’Oreal, Ranbaxy and LEO Pharma.