Inflammatory Role of Rosacea Pathogenesis

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Found this interesting information on the inflammatory theory of rosacea and would like the MAC MEMBERS to comment on whether they feel rosacea is indeed an inflammatory disease and whether this theory is more acceptable than the vascular disorder theory of rosacea? Here are the articles >

Rosacea is a Chronic Inflammatory Disease

While research has not completely ruled out a microbial component in the pathogenesis of rosacea (e.g., Demodex mite overgrowth), there is strong evidence that rosacea is primarily—if not solely—an inflammatory disease.

This view is supported by histopathologic findings that include follicular and perivascular leukocytic infiltrates1,2 and an absence of pathologic microflora.3 It is further reinforced by research demonstrating that the antibiotics effective against rosacea work by suppressing a variety of proinflammatory mediators thought to play a primary role in rosacea pathophysiology (Figure 1).4 These include tumor necrosis factor alpha (TNF-?), the interleukins IL-1 and IL-6, and the neutrophil-derived compounds nitric oxide (NO), matrix metalloproteinases (MMPs), and various reactive oxygen species (ROS).

Sequence of Events

While the evolution of the inflammatory response in rosacea has not been precisely elucidated, investigators suspect a sequence of events similar to the following:

Vasodilation of dermal capillaries, possibly mediated by histamine, prostacyclin, prostaglandin E2, nitric oxide, or other vasoactive compounds, causes initial erythema

Prolonged dilation weakens capillary walls, allowing neutrophils and proinflammatory cytokines such as TNF-?, IL-1, and IL-6 to leak into the surrounding dermis

Extravascular fluid builds up, overwhelming lymphatic vessels, and results in edema

Additional neutrophils are recruited by chemotactic factors released from inflamed dermal tissues

Activated neutrophils release degradative compounds, including matrix metalloproteinases (collagenases and gelatinases), reactive oxygen species, and nitric oxide—that exacerbate the inflammatory response and lead to tissue damage. > Source of this article

Examining Inflammation as a Common Factor in Theories of Rosacea Pathophysiology

By Dr. Joseph Bikowski

Joseph Bikowski, MD

Clinical Assistant Professor, Dermatology

Ohio State University

Columbus, Ohio

Director

Bikowski Skin Care Center

Sewickley, Pennsylvania

Rosacea is a common, chronic disorder affecting millions of patients annually. Some estimates report prevalence rates as high as 1 in every 20 Americans.1 While the signs and symptoms of rosacea have been established and documented, the exact pathophysiology of the disease has yet to be fully identified.1,2 Multiple theories have been suggested ranging from microbial causation to photodamage.2,3,4 However, no single etiologic source has been established. Without researched evidence of the etiology of rosacea, we must consider other available clues to help identify the underlying pathophysiology. The most reliable source of this information is derived from current treatment practices where it is believed that effective therapies for rosacea work by exerting anti-inflammatory effects.5,6,7 Therefore, it is necessary to examine the role of inflammation as a central causative factor of the signs and symptoms of rosacea.

The pathways of inflammation involved in rosacea have been documented to be from multiple physiologic sources. It is highly probable that these pathways work concomitantly to produce the common symptoms of rosacea such as inflammatory lesions, erythema, telangiectasias, phymatous changes, and ocular symptoms. This is supported by the fact that current therapies used to treat the disease work by interdicting multiple inflammatory pathways and yield improvement of varying degrees in each of the symptomatic areas.6,7,8, 9 Furthermore, the known anti-inflammatory properties of doxycycline (a common systemic therapy for rosacea) are closely correlated with the inflammatory mediators postulated to be responsible for the symptoms of rosacea.

Recent research has shown an increase of specific proinflammatory cytokines, including tumor necrosis factor (TNF-?) and interleukin (IL-1?), in biopsies of inflammatory lesions from acne patients.9 These cytokines trigger a chain of chemical responses in the body, including the release of certain matrix metalloproteinases (MMPs); specifically, MMP-1, -3, and -9.10,11 These MMPs are involved in collagen matrix degradation and inflammatory damage. The likely result is the development of papulopustular lesions. Owing to the similarities between these lesions in acne and rosacea, this evidence offers insight into the inflammatory nature of rosacea.

Two additional inflammatory mediators thought to incite the symptoms of rosacea are reactive oxygen species (ROS) and nitric oxide (NO). Clinical trial evidence reports that patients with severe rosacea have a reduced capacity to counter the negative effects of ROS; thus, experiencing an increased inflammatory response.11,12 This may also explain the connection between photodamage and rosacea since sun exposure is known to induce the release of ROS which subsequently activates MMPs.13 The role of NO involves vascular changes and is believed to be partially responsible for the erythema, edema, and telangiectatic symptoms of rosacea.11,13 Vasodilation plausibly results in vascular instability leading to increased vessel permeability, edema, and fixed vessels. This may worsen with increased sun exposure as an increase of NO in the keratinocytes has been linked with UVB rays.9

Substantiating each of the stated inflammatory mechanisms of pathophysiologic activity in rosacea is evidence that currently prescribed therapies do target these mechanisms. It is postulated that metronidazole and azelaic acid, both applied topically, reduce ROS and thereby decrease inflammation.6,7,15 Furthermore, doxycycline inhibits inflammation (directly and indirectly) by reducing the activity and/or expression of MMPs, TNF-? , IL-1?, NO, and ROS.8,11 These effects have been proven in anti-inflammatory doses of doxycycline which are devoid of antibiotic activity.8,16 Such activity results in improved integrity of the dermal tissue, reduced inflammation, and less vasodilation. Therapeutically, such effects appear to clinically reduce the numbers of inflammatory lesions, improve erythema, and help reduce the visibility and occurrence of telangiectasias. Hence, a comparison of available research regarding the pathophysiology of rosacea paired with the known activity of common treatments for this disease strongly point to inflammation as the central causative factor. This information is important to the development of future treatment options for rosacea as well as the appropriate selection of currently available treatments to ensure efficacious and safe therapies. > source of this article