Vol. 5 • Issue 2 • Page 13
The face is the first thing a person sees, casting impressions within seconds.
This is why rosacea, a chronic skin disorder primarily of the central face, can be so devastating for patients. Characterized by clinical signs of flushing, erythema, telangiectasia, papules, pustules, ocular lesions, and, in severe cases, rhinophyma, patients with rosacea often struggle with insecurities that affect their social and professional lives.
Unfortunately, physicians are not sure what causes this condition, leaving us with empiric treatment of its signs and symptoms. However, several treatment strategies, including lifestyle changes, topical medications and systemic medication, can help control these symptoms.
What is Rosacea?
To understand how to treat rosacea, we must first discuss its manifestation. The condition commonly strikes fair-skinned individuals in their thirties, but Asians and African American have also been known to develop rosacea. In addition, rosacea can strike at any age in both men and women. We are not sure of the true incidence of the condition, largely because it is not fully characterized. However, one epidemiologic study in Sweden showed a prevalence of 10 percent in the population.1
To provide guidance in treating the disease, The National Rosacea Society developed a standard classification system in 2002 to address the diversity of clinical manifestations, etiology and pathogenesis of rosacea.2The system describes the primary features of rosacea and defines four subtypes and one variant. (See Table 1.)
Patients need to display just one of these primary features, such as flushing (defined as transient erythema), persistent redness, papules, pustules and telangiectasia. In addition, secondary features may also occur in addition or alone. Secondary features include burning or stinging, elevated red plaques, dry skin, edema, ocular manifestations, and peripheral location and phymatous changes, such as rhinophyma.
Unfortunately, the pathogenesis of rosacea is still a mystery. Likely various etiologic factors come into play. We know, for example, that patients with rosacea often have abnormal vascular hyperactivity, as evidenced by facial flushing. Climate also seems to play a role, specifically exposure to the sun and extreme cold. For example, rosacea appears to be more prevalent in northern climates with frequent harsh climates. Some theories suggest that solar elastosis can alter connective tissue, which can reduce support to small vessels. This results in prolonged vasodilatation and secondary immune complex deposition, associated with the condition.
Another theory of rosacea is the pathogenic role of Demodex folliculorum. Demodex is a mite that lives primarily within the sebaceous follicles of the central face. More Demodex mites have been found in rosacea patients compared to normal individuals.3However, the increase in Demodex mites may actually be a side effect of the condition rather than a cause. It could also simply be an exacerbating factor in these individuals.
H. pylori is another microorganism that has been investigated for its possible pathogenic role. Support for this theory is considerably lacking, however. Most evidence now shows that the association is simply a coincidence of two common conditions that respond to similar therapies.
Recent evidence has also shown abnormally high levels of cathelicidin, antimicrobial peptides known to induce skin inflammatory responses, in the facial skin of rosacea patients in forms that are different from those present in normal skin. LL-37 was one of the main antimicrobial peptides found in rosacea, but not found to be abundant in normal skin. LL-37 was shown to induce erythema and vascular dilatation in vivo in mice, which demonstrates an association between the clinical presentation of rosacea and abnormal cathelicidin expression.4Since we don't have a complete understanding of rosacea's pathogenesis, we generally tackle specific symptoms rather than eradicating the disease. Unfortunately, rosacea tends to wax and wane despite therapy. As physicians, we need to provide a multifaceted approach.
Everyday Solutions
One of the easiest things for patients to do is to avoid triggers. Thus, patients may have to eliminate spicy foods and caffeine from their diets. In addition, stress, extreme temperatures, hot beverages and alcohol can cause flare-ups of the disease.
Patients should also use non-irritating, hypoallergenic, noncomedogenic creams, lotions, soaps and cosmetics to decrease the risk of irritation. I also suggest avoiding the sun and using sunscreen with an SPF of 30 or higher. Physical blockers such as titanium dioxide and zinc oxide are usually well tolerated. A sunscreen with a green tint may help improve the appearance of erythema as well.
Topical Measures
I often suggest topical medications to patients with mild-to-moderate cases of rosacea. These tend to have slower onset, but fewer safety concerns than oral medications. These measures can also help maintain remission.
I commonly prescribe topical metronidazole to treat rosacea. This works to combat inflammatory lesions and the inflammation that manifests in generalized erythema. Azelaic acid appears to be as effective as metronidazole.5The mechanism of action of azelaic acid is unknown, but it has been shown to possess antimicrobial activity against P. acnes.6
In other cases, I may suggest topical sodium sulfacetamide and sulfur preparations, but patients are often unhappy with the "rotten egg" odor associated with the products. Thus, I usually reserve this for patients who do not tolerate other therapies or recommend it as an adjunct for more severe disease.
In patients with inflammatory papules, benzoyl peroxide can also be useful, but many patients with rosacea find it irritating. An alternative would be topical antibiotics, such as erythromycin or clindamycin, which have also been shown to decrease the inflammation associated with rosacea.
A newer trend on the market is topical combination products that combine benzoyl peroxide with antibiotics such as clindamycin or erythromycin. These products allow for better compliance and ease of use. Finally, tretinoin has also been used in rosacea with some success.
Some over-the-counter products may also give relief. Recent clinical trials conducted at the University of California, Irvine have studied the effectiveness of a new moisturizing lotion, Pyratine XR™ (0.125%) for improving the signs and symptoms of rosacea.
Pyratine-6 (Furfuryl tetrahydropyranladenine) is a plant cytokinin that has growth modulatory, anti-oxidative and anti-senescent effects on human skin cells.7Studies show this product also improves the signs and symptoms of rosacea-as well as benefit photodamaged skin.8In one study, more than 50 percent of subjects with rosacea showed improvement as early as four weeks. After 12 weeks of treatment, 80 percent of the subjects showed overall clinical improvement in rosacea. There was a 30 percent decrease in total lesion count by week four and a 40 percent decrease after 8 to 12 weeks of treatment. Erythema was reduced by 17 percent in 12 weeks, and telangiectasia by 12 percent. More recent findings, presented at the Annual Meeting of the American Academy of Dermatology this year, also showed progressive improvement in erythema, lesion counts and telangiectases without any adverse effects with continued use.
Some other products currently under development for the treatment of erythema associated with rosacea include Sansrosa™ and oxymetazoline. The active ingredient in Sansrosa™ is brimonidine, an alpha2-adrenergic receptor agonist, which works as a vasoconstrictor. Therefore, brimonidine can be toxic when there are high levels of systemic absorption. A phase II clinical trial tested the bioavailability of brimonidine when applied topically to diseased rosacea skin. The results of this trial have not yet been released. However, a patent application for brominidine appears to have been filed.
Oxymetazoline is an alpha1-adrenergic receptor agonist that has had some promising results in improving the erythema in rosacea. However, researchers have yet to perform large clinical trials.
Systemic Therapies
Systemic therapies are effective for rosacea because they have a more rapid onset. However, I reserve this treatment for more severe cases, including inflammatory lesions, ocular rosacea, flushing or recalcitrant cases. These medications carry potential side effects, including gastrointestinal upset and candida. We also have to use caution prescribing these drugs to women who are pregnant or who may be getting pregnant.
Oral antimicrobials help to control rosacea through their anti-inflammatory properties rather than their antibacterial effects. Higher doses are initially used to get the disease under control and then tapered down to a maintenance dose to minimize these side effects. The optimal goal is to completely transition patients onto topical treatments since unnecessary high doses and/or extended courses of antibiotic can cause antibiotic resistance.
Newer formulations of antibiotics work to solve this problem. These drugs are low dose and extended release. Because they are sub-antimicrobial, they decrease the chance of antibiotic resistance, but they still provide the anti-inflammatory properties. Commonly used antibiotics for inflammatory lesions or ocular rosacea include erythromycin, azithromycin, tetracylcines, minocycline, doxycycline and metronidazole. Oral isotretinoin is reserved for severe or recalcitrant forms of rosacea associated with inflammatory lesions. The duration of its effect can be variable. Medications to reduce flushing such as beta-blockers, clonidine, naloxone and SSRIs can be useful, but they all have side effects that must be weighed.
Vascular laser therapy is considered the mainstay of treatment for telangiectasia and rhinophyma and may also be effective for reducing erythema. For example, pulsed dye lasers target oxyhemaglobin in telangiectasias, which are mostly unresponsive to topical and oral therapies. Pulsed dye lasers cause vessel reduction with minimal damage to surrounding tissues. Another laser modality, intense pulsed light (IPL), targets hemoglobin, making it effective in treating telangectasia. However, with the natural progression of aging, new vessels develop.
Nonablative lasers may also be effective in rosacea by improving the epidermal barrier and remodeling of dermal connective tissue. In addition, another common component of the condition, rhinophyma, can be resurfaced by mechanical dermabrasion, carbon dioxide laser, electrocautery, paring with a scalpel, or excision with skin grafting.
As stated previously, current therapy aims at treating individual elements of rosacea. This usually means that more than one therapy is generally used simultaneously. Therapies should be tailored to the particular symptoms of the patient and their own preferences.
Associated Table 2
References
1. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol 1989; 69: 419-23.
2. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, Powell F. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002; 46: 584-7.
3. Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy. Br J Dermatol 1993; 128: 650-9.
4. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner RA, Bonnart C, Descargues P, Hovnanian A, Morhenn VB, Gallo RL. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 2007; 13: 975-80.
5. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol 1999; 40: 961-5.
6. Leeming JP, Holland KT, Bojar RA. The in vitro antimicrobial effect of azelaic acid. Br J Dermatol 1986; 115: 551-6.
7. Data on file, Senetek PLC, Napa, CA.
8. McCullough JL, Garcia RL, Reece B. A clinical study of topical Pyratine 6 for improving the appearance of photodamaged skin. J Drugs Dermatol 2008; 7: 131-5.
Arisa Ortiz, MD, is a clinical research fellow at University of California Irvine's department of dermatology. She has been an investigator in more than a dozen clinical research trials and has an extensive academic background in both basic and clinical research. Disclosure: Dr. Ortiz indicates that she is a researcher on a clinical trial for Senetek PLC. The company's product, Pyratine, is mentioned in this article.
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