The Proposed Inflammatory Pathophysiology of Rosacea: Implications for Treatment

Larry Millikan, MD

Disclosures

Skinmed. 2003;2(1) 

In This Article

Rosacea as an Inflammatory Disorder

As rosacea progresses, inflammatory lesions (papules and pustules) become evident. These lesions are almost always follicular in origin, affecting both sebaceous and hair follicles.[5] Unlike acne vulgaris, however, inflammatory rosacea is not a bacterial disease of the pilosebaceous unit.[2,8] Comedones are usually not present, and only normal bacterial flora have been demonstrated in skin samples taken from patients with rosacea.[2,5,8] The inflammatory stage of rosacea could be considered a form of chronic sterile cellulitis (Figure 4).[6]

Recent flare of erythema "juicy" nodules and pustules, only responding to systemic steroids.

As noted, inflammatory mediators may be operative in the vasodilation seen in rosacea patients. Inflammatory mediators such as substance P, histamine, serotonin, bradykinin, or prostaglandins have been implicated.[5,11,19]

Tissue damage caused by photoaging also contributes to the development of both vascular and inflammatory rosacea. Actinic degradation of vascular and perivascular collagen and elastic tissues directly weakens the mechanical integrity of blood vessels and increases the hyper-responsiveness of facial microvasculature (Figure 5).[6,8]

Severe flare of papules and pustules in early pregnancy.

The ensuing inflammatory processes play a pathogenic role in the development of erythema and telangiectasia, as well as inflammatory stigmata.[6] Degradative enzymes, including proteases, such as elastase, are released from activated neutrophils attracted to the area, further degrading the connective tissue surrounding blood vessels.[6]

Angiogenesis triggered by the inflammation may also be involved in the development of telangiectases. Angiogenic factors stored in extracellular matrix may be released by neutrophilic proteases, or released and activated by macrophages.[6]

Solar elastosis can also lead to lymphatic failure.[6] When the volume of protein exudate exceeds lymphatic drainage, extracellular fluids accumulate in the superficial dermis.[17] The result is self-sustaining cutaneous edema and inflammation, which frequently precede the development of connective tissue hypertrophy.[6] Attracted neutrophils release proteins that degrade matrix proteins, leading to fibroplasia, a precursor to rhinophyma.

The Role of Neutrophils. The intimate relationship between the vasculature and the immune system, as well as the success of anti-inflammatory agents in the treatment of rosacea, suggests that inflammatory cells such as neutrophils, and other inflammatory mediators, are key pathophysiologic factors in the development of rosacea[21] (Figure 6). The stigmata of rosacea may be manifestations of an inflammatory process: neutrophilic dermatosis.[21] Therefore, pharmacologic modulation of neutrophilic function is critical to the resolution of rosacea.[22]

Proposed inflammatory pathophysiology leading to symptoms of rosacea.

How Treatment Targets Inflammatory Events.As noted, topical metronidazole and certain systemic antibiotics constitute first-line therapy for rosacea. Oral tetracycline, doxycycline, and minocycline have been used for the treatment of rosacea. The efficacy of oral antibiotics is thought to be due more to anti-inflammatory rather than antibiotic effects.[1] Other traditional topicals that have been used "off label" include clindamycin, sulfacetamide, and sulfur, and their mechanism is less obvious.

Topical metronidazole, developed in response to concerns generated by chronic systemic antibiotic therapy, is the mainstay of rosacea therapy.[2,3,23,24] Like systemic antibiotics, the in vitro actions of topical metronidazole include anti-inflammatory as well as antimicrobial actions.[2,8,25] The efficacy of metronidazole in rosacea is believed to be due primarily to its modulation of neutrophilic activity, including inhibition of reactive oxygen species.[21,22] Thus, metronidazole blocks the cascade of inflammatory processes that appear to cause and sustain rosacea symptoms.

The first available formulation of topical metronidazole was an aqueous gel. Metronidazole 0.75% in a gel formulation has demonstrated efficacy in reducing the erythema and inflammatory lesions of rosacea.[23] One recent study[24] demonstrated that continued treatment with topical metronidazole gel maintains remission of moderate to severe rosacea when first achieved by treatment with oral tetracycline and topical metronidazole gel.

Although the aqueous gel is well tolerated, other formulations including metronidazole lotion (0.75%) and cream formulations in 0.75% and 1.0% concentrations were developed for patients with rosacea who have unusually sensitive skin. All formulations of topical metronidazole are well tolerated.[1,23,25,26,27]

In a head-to-head comparison, once-daily application of either 0.75% or 1.0% creams achieved comparable reduction of erythema and inflammatory lesions. This allows the practitioner flexibility in prescribing. Both formulations reduced the median number of papules and pustules by approximately 60%, and the erythema by 26%-30%.[27]

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