Important Concepts About Rosacea
Rosacea is histologically similar to acne1 and can have distinct morphologies, but the important concepts to keep in mind are that:
1. There is no diagnostic laboratory test that can confirm or exclude rosacea.
2. There is a difference between flushing and blushing.
3. Redness that stays put and does not change is not rosacea.
4. At least one or more of the following criteria for diagnosis must be met:
– flushing (transient erythema)
– nontransient erythema as a baseline
– papules and pustules
Establishing a Diagnosis
Rosacea is a clinical diagnosis simply based on history and physical exam findings.
In April 2002, a standard classification of rosacea was published in the The Journal of the American Academy of Dermatology (JAAD)
.2 This consensus publication served to report the classification and staging of rosacea as determined by the National Rosacea Society Expert Committee.
The morphological diagnostic criteria were reviewed and the committee determined the following definitions of descriptive terms (Table 1
). Dermatologists often classify the stage of rosacea based on these criteria, but it is often different than acne, for which lesion counts often serve as a measure of therapeutic success.
Causes of Rosacea: Structure vs. Function
From here, the questions of a true cause comes down to the effects of the components of the skin (structure) in balance to the dynamic characteristics of the disease (function). These can be classified further by evaluating the possible combination of mechanisms.
The vascular component of rosacea involves vasodilation from thermal and climatic stimuli as well as neurological input. This can explain why patients often notice flushing from weather and temperature changes, a seasonal predominance to flares, or even flare-ups experienced after a warm weather vacation during winter. Moreover, extravasation of plasma during blushing can be an additional source of vascular instability and contributing factor of symptoms. An often overlooked historical trigger of flushing or vascular instability may also be iatrogenic, specifically the use of niacin for hyperlipidemia or previous use (or misuse) of topical steroids.3,4,5
The mechanisms of rosacea involving the facial vasculature reflect a combination of humoral and neural stimuli. Changes that promote facial blood flow and flushing involve a baseline flow increased over body flow. From a structural view, the contributing vessels are typically larger and closer to the skin’s surface.
What are the correlations to a patient’s symptoms? Consider the responses to thermal stimuli such as coffee or other hot beverages. When ingested, there is an increase in the temperature of the mouth and oropharynx, which creates feedback to the carotid body and a compensatory attempt to regulate the heat. This occurs by messages sent to the hypothalamus to trigger vasodilation to dissipate the warmth. There is also a physiological response to shunt blood from face to brain for these events to occur. However, it has been hypothesized that rosacea patients lack this response, which in turn leads to flushing.
Other Structural Changes
Aside from the vascular contribution, there are other structural changes in the dermis that can be significant in the pathogenesis of rosacea. Sebaceous hyperplasia is a common finding, although, paradoxically, most rosacea patients often do not complain of being oily. Photodamage is also an exacerbating factor of the symptom complex in many patients, but can often be a limitation in response to therapy due to poor wound healing and relative loss of immune mediation. Histologically, there is gradual matrix degeneration and an alteration in the distribution of vasculature and nerve bundles.6
Despite these structural changes, the erythema of rosacea involves many functional components, many of which are the result of dermal inflammation. There are balances of inflammatory mediators that are at play (Table 2
) that can be influenced by therapies, but without an understanding of their mechanism of action the patients’ treatment protocol may not be effective.
Patient History: Are We Asking the ‘Burning Questions?’
The history is probably the most important part of the assessment of the rosacea patient, especially when considering how many of these patients are misdiagnosed or are unresponsive to their treatments. Aside from exclusion of triggers and response to previous therapies, there should be an overall questioning to exclude or confirm the diagnosis.
Several important questions include:
1. Is a history of flushing in a central facial distribution enough to define rosacea?
2. How long does the transient erythema of the flush persist?
3. Are facial papules and pustules in a central facial distribution characteristic enough?
4. How long does the nontransient erythema persist?
According to the expert panel, the most important finding is persistent erythema of the central portion of the face lasting for at least 3 months.2
Flushing vs. Blushing
Flushing is prolonged in rosacea patients, although many people without rosacea experience evanescent flushing in response to embarrassment, exercise, hot environments, a glass of wine or other triggers. However, while blushing is often short and transient, flushing typically lasts longer than 10 minutes. Such a prolonged vasomotor reaction may help in differentiating physiologic flushing from that seen in rosacea patients.1,2
Is Rosacea a Pilosebaceous Disorder?
There are structural changes in rhinophyma that are unique both clinically and histologically. A study published by Marks et al involved histological study of rosacea patients with either papular stage (PPR) or telangiectasia (ETR). There were 108 rosacea patients biopsied, 74 of whom had papules. The results showed that only 20% of papules had follicular origin, while 51% had peri-adnexal infiltrates. While no role of P. acnes was demonstrated, Demodex was suspected as a possible trigger of dermal inflammation by inducing a hypersensitivity response similar to that seen in scabies.4
Is Rosacea an Infection?
Rosacea has been characterized as an inflammatory disorder, but questions still arise about a potential infectious agent, specifically Demodex folliculorum, Bacillus oleronius, and Helicobacter pylori.There are many theories on the role of these agents but none have elucidated a clear role as a trigger.
In another study, 38 patients with rosacea were matched with 38 age-and-sex-matched healthy subjects. Biopsy samples were taken from three facial sites assessing mite positivities, the mean mite counts in both study groups, the mean mite densities at each facial site and in the rosacea subgroups, and the mite densities above 5/cm2. The results of the study revealed that the mean mite count in the rosacea group (6,684) was significantly higher than that in controls (2,868; P < 0.05). The cheek was the most frequently and heavily infested facial region. Ten rosacea patients and five normal subjects had mite densities over 5/cm2 and the difference was not statistically significant (P > 0.05).3
There are several important points to remember about Demodex spp. in the rosacea patient. Demodex spp. mites are found in a large number of healthy persons, although more commonly in older patients, and they become pathogens after they multiply and invade the dermis, which creates an inflammatory response.7 Aside from rosacea, it has been implicated in folliculitis, dyschromias, pityriasis folliculorum and blepharitis. Finding Demodex is not proof of pathogenesis of these conditions, and it is the density of mites or their extrafollicular location that induces hypersensitivity.3
Helicobacter pylori is another infectious agent that was thought to be a pathogen in rosacea. In the past, patients with active gastrointestinal H. pylori infection confirmed by the urea breath test and the concomitant finding of rosacea were treated with the intent to eradicate H. pylori. However, treatment and/or eradication of H. pylori confirmed by the negative findings of the urea breath test did little more for the rosacea of patients than the placebo effect observed with the control cohort. Helicobacter pylori and its eradication in Rosacea was studied by Szlachcic A et al.8 Patients included in the study reported symptoms closely related to gastritis, especially involving the antrum mucosa, with elevated plasma levels of TNF-alpha and IL-8. The eradication of H. pylori lead to reduction of symptoms of rosacea, gastritis, hypergastrinemia and gastric acid secretion. This observation led to the possibility that extra-gastric symptoms of H. pylori infection might be mediated by H. pylori-related cytotoxins and cytokines. However, these presumed associations about Helicobacter pylori between rosacea and gastrointestinal diseases were refuted by the findings that elevations in Gastrin caused fluctuations in skin temperature and vasomotor instability, but the GI symptoms linked to hypochlorhydria, gastritis, and abnormal jejunal mucosa were no more common in patients without rosacea.8
Correlations to Topical Therapy
When dermatologists are choosing topical therapies appropriate for rosacea patients, the active ingredient, vehicle, and frequencies of application all contribute to outcomes. However, patients often forget that avoidance of triggers is probably the most important therapy.
Topical metronidazole has been traditionally one of the most frequently used therapies for rosacea by all physicians, but how does its mechanism affect the disease? Its mode of action appears to be anti-inflammatory and anti-oxidant,9 which would consequently result in reduction in neutrophil-generated reactive oxygen species (ROS). This may have its primary benefit in inflammatory stages of rosacea by inducing a reduction in lesions, symptoms and erythema.10
Azelaic acid is a versatile treatment for all stages of rosacea, although the mechanisms apply best to reduction in erythema and papular component of rosacea, as well as its off-label uses in acne and melasma, given the inhibition of tyrosinase. In vitro the molecule acts as free radical scavenger, it inhibits oxy-radical toxicity to neutrophils, and as a result creates a reduction of reactive oxygen species diminishes potency of inflammation.10,11,12
Retinoids traditionally have not played a significant role in the treatment of rosacea, mainly out of concern for irritation to the labile skin of the typical patient. However, given that the prominent histologic features of rosacea involve dermal inflammation, elastin and collagen degeneration, and alteration of the cutaneous vasculature, long-term maintenance of the older rosacea patient with concomitant photodamage might include topical retinoids. Although their clinical response is delayed, often not evident until 2 or more months into therapy, the benefits of changing the architecture of the epidermis and modulating inflammation of the dermis may outweigh the potential for irritation and complicating the regimen. This could be supported by the observation that topical tretinoin promotes connective tissue remodeling in the papillary and reticular dermis and minimizes dermal inflammation with chronic therapy.1,6,13
Our traditional approaches to the assessment and topical management of rosacea may need adjustments to include avoidance of triggers and optimizing the mechanisms of action. The importance of a history to exclude the diagnosis as well as assess the patient for other therapies such as antibiotics, light therapies and systemic retinoids cannot be undervalued in the long-term management of these patients.
References1. Powell FC. Rosacea. N Engl J Med. 2005;352(8):793-803.2. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. JAAD. 2002;46:584. 3. Wilkin JK. Rosacea: Pathophysiology and treatment. Arch Dermatol. 1994;130(3):359-362. 4. Marks JN et al. Harcourt-Webster Histopathology of rosacea. Arch Dermatol. 1969; 100: 683-91.5. Yamasaki K, Di Nardo A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-980. 6. Oztas MO, et al. The role of free oxygen radicals in the aetiopathogenesis of rosacea. Clin Exp Dermatol. 2003;28(2):188-192. 7. Erba_ci Z, Int Ozgoztasi O. The significance of Demodex. folliculorum density in rosacea. J Dermatol. 1998; 37:421-5.8. Szlachcic A, Sliwoski Z, Karczewska E, et al. Helicobacter pylori and its eradication in rosacea. J Physiol Pharmacol. 1999; 50:777-86.9. Miyachi Y. Potential antioxidant mechanism of action for metronidazole: implications for rosacea management. Adv Ther. 2001;18:237-243.10. Del Rosso JQ. Medical treatment of rosacea with emphasis on topical therapies. Exp Opinion Pharmacother. 2004; 5:5-13.12. Kayne, A, Intendis Pharmaceuticals, anecdotal.13. Zouboulis CC. Retinoids — which dermatological indications will benefit in the near future? Skin Pharmacol Appl Skin Physiol. 2001;14:303-15.