Unlocking the mysteries of rosacea
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Molecular studies highlight possible pathways in pathophysiology

An estimated 16 million Americans have rosacea, one of the most common dermatoses of adults. Yet most of them don’t know they have it, and only a small fraction are receiving treatment, according to the National Rosacea Society (NRS). The disease is not life-threatening, but those who suffer from even the mildest form of rosacea report that it extracts a significant toll on their social and emotional well-being. According to results of a recent NRS survey of 801 rosacea patients, a strong majority of patients in all subtypes (ranging from 61 percent of those with erythematotelangiectatic rosacea to 85 percent of those with phymatous rosacea) said the disease had inhibited their social lives. The most common complaint was having to refuse food or drink for fear of triggering a flare-up, but respondents also cited receiving negative comments or stares and cancelling social events because of self-consciousness regarding their appearance. 

Rosacea’s impact on patients’ quality of life underscores the importance of understanding the disease and finding more effective treatments. Despite its prevalence, the etiology and pathophysiology of rosacea, as well as the cure, have remained a mystery. It’s also unclear whether the four subtypes of rosacea, defined by an NRS committee of experts and described in the Journal of the American Academy of Dermatology (2002;46(4):584-87), truly represent a “march” from one stage to the next. Research conducted in the past few years is honing in on dysfunction of the innate immune system as an underlying factor, and also examining the role of inflammation and neuroimmune communication. The role of the Demodex mite remains under scrutiny, with topical ivermectin now being investigated as a possible treatment. In the meantime, as researchers have continued to test new therapies for rosacea, an agent that has proven effective against one of its most recalcitrant symptoms —  the redness associated with erythematotelangiectatic (subtype 1) rosacea  — may soon be available to patients. [pagebreak]

A once-daily solution for redness

The erythema of the central face that characterizes rosacea is thought to result from abnormal cutaneous vasomotor activity, according to a British Journal of Dermatology article (2012;166:633-41) describing two phase 2 studies of a topical gel with vasoconstrictive activity. Brimonidine tartrate (BT) is a highly selective alpha2-adrenergic agonist that has been used for about 10 years as an ophthalmic solution for the treatment of glaucoma, said the study’s first author, Joseph F. Fowler Jr., MD, clinical professor of dermatology at the University of Louisville. “It’s been investigated as a treatment for rosacea for probably six or eight years. Our studies looked at several dosage levels, as well as once-daily and twice-daily treatments, and compared the results with those of vehicle gel,” he noted. “ We found that the highest dosage [0.5 percent] when given once a day, seemed to work better than the lower or middle dosages, even when those were given twice a day.” In both studies, the once-daily application of BT gel provided significantly greater efficacy and faster onset of action than vehicle gel, without evidence of tachyphylaxis, rebound, or aggravation of other clinical signs of rosacea. In the first study, in terms of a one-grade improvement on both a clinician’s and a patient’s assessment (on a scale of 0, clear skin to 4, severe erythema), the responder rate was 84 percent, 81 percent, and 75 percent for the three dosage levels of BT gel vs. 28 percent for the vehicle gel. In the second study, in which the profile of success was defined as a two-grade improvement in clinicians’ and patients’ assessments over 12 hours, the success rate of BT 0.5 percent once daily at three, six, nine, and 12 hours on day 29 was 30 percent, 28 percent, 32 percent, and 19 percent, respectively (vs. 4 percent, 7 percent, 4 percent, and 4 percent for vehicle gel once daily). All dose regimens of BT gels were safe and well tolerated during four weeks of continuous application. One subject requested discontinuation because of mild skin burning. [pagebreak]

“We’re relatively good at suppressing the inflammatory components of rosacea, but up until now, we really didn’t have anything that would help much with the erythema,” Dr. Fowler said. “This will be the first actual treatment for erythema outside of laser procedures or cover-up with cosmetics. And it’s kind of nice that we’ve got a new chemical in dermatology instead of a repackaging of a previous drug.” Phase 3 testing of BT gel has been completed, and the results were recently published in the Journal of Drugs in Dermatology (2013;12(6):650-656). Dr. Fowler said the drug has been submitted to the U.S. Food and Drug Administration for approval.

Regarding the role BT gel might play in the long-term management of rosacea, Dr. Fowler said that for most patients, he envisions its daily use to treat erythema, “and then if and when they have some inflammatory lesions, they would use treatments we know are effective: systemic antibiotics, like doxycycline; topical azelaic acid; metronidazole in a variety of preparations, and others. They might go on and off the inflammatory treatments according to need and stay on the erythema treatment as long as they’re concerned about the redness.” Brimonidine begins to reduce redness as soon as 30 minutes after application, and “probably has its maximum effect somewhere between six and 12 hours,” Dr. Fowler said. “So if you have a day when you really don’t care if your face is red — say you don’t plan to go out  — you might not use it that day. And that seems to be perfectly fine; if you use it the next day, it works just as it did the previous day.”

Another vasoconstrictor, oxymetazoline, is currently under investigation in a cutaneous gel formulation, Dr. Fowler said. An alpha-1 and partial alpha-2 receptor agonist, it is currently available as an over-the-counter decongestant in the form of a nasal spray. Case reports have indicated that oxymetazoline is effective in reducing facial erythema, but phase 2 trial results have not yet been published. [pagebreak]

Antimicrobial peptides and innate immunity

A prominent researcher with a special interest in innate immunity was taken by surprise, he said, when he discovered that the skin of rosacea patients expresses excessive cathelicidin and its activating enzyme, kallikrein-related peptidase 5 (KLK5). “Overproduction of these seem to be triggered by a lot of environmental events [in rosacea patients],” said Richard L. Gallo, MD, PhD, professor of medicine and pediatrics and chief of the division of dermatology at the University of California, San Diego. “We’re all exposed to microbes, mites, ultraviolet light, and spicy foods. If everyone is exposed to all of these things, what are the genes that are hyperreactive that lead to rosacea? That’s what these really are, the genes that are reacting to these environmental events.”

In an article published in the Journal of Allergy and Clinical Immunology (2008;122(2):261-66), Dr. Gallo and co-author Jurgen Schauber, MD, describe cathelicidins as “unique antimicrobial peptides that protect the skin through two distinct pathways: direct antimicrobial activity and initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization.” The article implicates cathelicidin peptides in atopic dermatitis and psoriasis, as well as rosacea, and notes that in patients with rosacea, they result from a posttranslational processing abnormality associated with an increase in protease activity in the epidermis. In mice, Dr. Gallo explained, “you can put the cathelicidins and KLK5 on the skin, and they will develop redness and extra blood vessels that look like a patient who has rosacea. So that’s part of the proof of the hypothesis. The next step is to test in patients, and find out: If you block their action, will patients improve?” 

Interrupting the pathway can involve blocking the gene’s ability to make the peptide or, alternatively, blocking the function of the peptide molecule, Dr. Gallo said. “And that’s where we are today. We’ve just had a study accepted by JAAD that looks at whether or not existing medications used in the treatment of rosacea might be having a beneficial effect by acting on this pathway. We hypothesized that azelaic acid, even though we didn’t know it could do this, may be able to block that pathway —  and maybe that’s the reason it works.” In a 16-week, multi-center trial involving 60 patients with mild papulopustular rosacea, “we found that azelaic acid did in fact block the pathway, we think by inhibiting the KLK enzyme.” Another study of 160 patients receiving slow-release, low-dose doxycycline tested the same hypothesis and the results of this study are currently under analysis, Dr. Gallo said. (The azelaic acid study was funded by Bayer; the doxycycline study was funded by Galderma.) [pagebreak]

“When we measure these pathways in patients, we see different groups, so we’re getting biomarkers of disease,” Dr. Gallo said. Although the presence of biomarkers has not yet been matched against the genetic profiles of rosacea patients, “that’s what this data is supporting. All the studies to date are suggesting that once we understand enough about this, and we’re getting close, this will enable us to test the patient first and maybe predict what will be the best therapy. Right now we’re kind of at the cusp of being able to develop new treatments.”

The role of neurotransmitters

Another pioneer in the field is Martin Steinhoff, MD, PhD, professor of dermatology at the University of California, San Francisco, who has focused on the role of neurotransmitters in rosacea. “We study the interaction between the vascular system, the immune and the nervous system, and we have also studied in detail the genes which are upregulated or downregulated, and compared this to the skin morphology in the different subtypes of rosacea,” Dr. Steinhoff said. “So far we were a little bit in the dark; because we didn’t know which were the principal cells involved, and the principal mediators that drive the initiation of rosacea.” With particular interest in the flushing (erythema) that characterizes the early stages of rosacea, Dr. Steinhoff sought to understand what underlies the dysregulation of vasodilation and discomfort in rosacea patients. “We have some information from our gene studies, and currently we analyze the pattern of the more than 300 different genes we found to be involved,” he noted. “Now we know the critical immune cells and genes involved that include neuromediators, cytokines, chemokines, and proteases, for example.” 

One neuromediator, pituitary adenylate cyclase activating polypeptide (PACAP), was found to be “20 to 30 times upregulated in rosacea, and we know that PACAP is one of the most potent vasodilators in humans, so if we put this together we have lots of evidence that this mediator and/or its receptor plays a role in the early phase of rosacea,” Dr. Steinhoff said. In a study published in the Journal of Investigative Dermatology (2012;132(4):1253-62), Dr. Steinhoff and co-authors in Germany and France demonstrated the involvement of certain calcium ion channels in the pathophysiology of rosacea. “These also regulate vasodilation as well as inflammation and skin discomfort and many of them are activated by the trigger factors of rosacea, such as temperature changes, spicy food, ethanol, UV light, and exercise,” he explained. “So, we anticipate that dysregulation of ion channels may be at least involved in the flushing during the early stage of rosacea. Some of these ion channels are also upregulated in the gene array studies and are highly expressed on nerves in rosacea patients.” Understanding the key mediators and receptors involved in rosacea will lead to more targeted therapies with fewer side effects, Dr. Steinhoff said, and antagonists that act against those calcium channels and selected vasomediator receptors are currently under investigation. [pagebreak]

Does rosacea march?

Dr. Steinhoff’s research has also shown that rosacea subtypes 1, 2, and 3 “have clear differences with respect to which kinds of genes are most upregulated,” he noted. “So we continue to confirm that these are different subtypes, but it’s also interesting that there are some genes that overlap, and so it looks like there is a march from one subtype to the next. Eighty percent of the genes are different, but 20 to 30 percent are identical. So I would say there are two different forms of rosacea: one in which there is a march from subtype 1 to subtype 2 to subtype 3, and another, mostly in male patients, where you don’t see clinical manifestations of the first two subtypes” before phymatous rosacea occurs, although biopsy reveals inflammatory infiltrate and dilated blood vessels. “That tells us that people with rhinophyma who say they didn’t have the early stages of rosacea probably did, but it wasn’t clinically visible.”

Dr. Gallo noted that rosacea can progress from one subtype to the next, “but it doesn’t have to. It’s genetics that halts the progression, and if you get effective therapy you’re less likely to get more severe disease. But there’s also a school of thought that says some people with central redness of the face are misdiagnosed with rosacea, and it’s actually a separate type of disease that we can’t yet distinguish from rosacea.”

Fighting skin barrier dysfunction

Patients with rosacea frequently complain of dry, sensitive skin and often report burning and stinging sensations. In the view of a leading European rosacea expert, “all patients with erythematotelangiectatic and papulopustular rosacea have skin barrier dysfunction.” Frank C. Powell, MD, consultant dermatologist at Mater Misericordiae University Hospital in Dublin, Ireland, has studied the skin surface layer in rosacea and found that patients with papulopustular rosacea have reduced surface hydration levels in the presence of normal sebum casual levels, indicating that it may be the quality and not the quantity of sebum that plays a role in their rosacea. His group’s analysis of the sebaceous fatty acid composition of 25 patients with papulopustular rosacea and 24 age- and sex-matched controls, published in the BJD (2012;166(2):279-87), found that the rosacea patients had an abnormal sebaceous fatty acid composition, with reduced levels of long chain saturated fatty acids. To combat the effect of barrier dysfunction, Dr. Powell recommends that his patients avoid products with perfume, color, or alcohol, and moisturize daily. “In addition, because most are fair-skinned and sun-sensitive, they need to apply a sun block cream,” he added. “For simplicity, I advise the moisturizer be applied at night and the sun block in the morning.” [pagebreak]

Although the skin care recommendations for rosacea patients are fairly simple and straightforward, “a lot of patients, left to themselves, don’t wash enough because their skin is sensitive, and feels dried out and burned,” said Mark Dahl, MD, professor of dermatology at the Mayo Clinic College of Medicine in Scottsdale, Ariz. and chair of the NRS Medical Advisory Board. “And they don’t moisturize, because papules and pustules of rosacea remind patients of the oily skin acne they had as teenagers. Plus, when barrier function is defective, as it is in rosacea, moisturizers tend to sting. Patients think stinging moisturizers are irritating their sensitive skin. Yet daily applications of a moisturizer are an important part of therapy. Barrier repair requires proper cleansing and regular applications of moisturizers and emollient sunscreens. Usually redness improves and stinging lessens within two months.”

Editor’s note: Dr. Fowler received grants from Galderma Research and Development, Inc. to conduct studies of brimonidine tartrate.