Rosacea, an infectious disease: why rosacea with papulopustules should be considered a demodicosis. A narrative review.

Rosacea and demodicosis are common facial conditions in dermatology practice. While demodicosis is clearly the result of Demodex mite infestation, the pathogenicity of rosacea is still not sufficiently explained, so that it is defined by its symptoms, and not by its cause. It is usually considered as a disease of the immune system associated with neurogenic inflammation triggered by various factors (ultraviolet light, heat, spicy food, alcohol, stress and microorganisms). Its links with demodicosis remain controversial, although there is increasing evidence that Demodex mites may play a key role in the inflammatory process. Indeed, high Demodex densities are observed in nearly all cases of rosacea with papulopustules (PPR) and the papulopustules of rosacea can be effectively treated with topical acaricidal agents. Recent studies suggest that Demodex induces two opposite actions on host immunity: a defensive immune response aimed at eliminating the mite and an immunosuppressive action aimed at favouring its own proliferation. Moreover, the initial defensive immune response is likely diverted towards benefit for the mite, via T-cell exhaustion induced by the immunosuppressive properties of vascular endothelial growth factor, which may also explain the favourable influence that the altered vascular background of rosacea seems to exert on Demodex proliferation. In this review, the evidence for and against a causal role of Demodex in rosacea is discussed, applying three systems traditionally used to attribute causality to a disease (modified Koch criteria, Hill criteria for causality and Rothman model). The findings suggest that PPR can reasonably be attributed to Demodex proliferation, which appears to be a necessary factor in the centre of a causal network in which multiple co-factors interact and influence the occurrence and severity of inflammatory symptoms, from limited (pityriasis folliculorum) to more marked (PPR). PPR could, therefore, be considered as a chronic infection by Demodex mites with associated T-cell exhaustion.

Treatment of rosacea and demodicosis with benzyl benzoate: effects of different doses on Demodex density and clinical symptoms.

BACKGROUND: Patients with rosacea or demodicosis have high facial skin Demodex densities (Dds). Topical ivermectin, benzyl benzoate (BB) and crotamiton have been shown to decrease Dds in vivo, but there are few data on the clinical and acaricidal effects of BB among patients with rosacea. OBJECTIVE: To evaluate the impact of topical BB (+crotamiton) treatment on Dds and clinical symptoms of rosacea and demodicosis, and compare three BB treatment regimens. METHODS: In this retrospective observational study, 394 patients (117 with rosacea, 277 with demodicosis) were included. Three BB (+crotamiton) treatment regimens were compared: 12% once daily, 12% twice daily and 20% once daily. Dds were measured using two consecutive standardized skin surface biopsies [superficial (SSSB1) and deep (SSSB2)] before treatment and at the first follow-up. Symptoms were evaluated using investigator global assessment. Treatment was considered effective if the Dd had normalized (SSSB1 ≤ 5 D/cm2 AND SSSB2 ≤ 10 D/cm²) or symptoms had cleared and curative if the Dd had normalized and symptoms had cleared. RESULTS: At an average of 2.7 months after treatment start, the total Dd (SSSB1 + 2) had decreased by 72.4 ± 2.6% from the initial value across the whole cohort. Dds had normalized in 139 patients (35%), and symptoms had cleared in 122 (31%). Treatment was effective in 183 (46%) patients and curative in 78 (20%). Compliance was good: 77% of patients correctly followed treatment instructions. Results were similar in patients with rosacea and those with demodicosis. The 12% once-daily regimen was less effective than the other doses and had poorer compliance than the 12% twice-daily regimen. CONCLUSION: Topical treatment with BB (+crotamiton) may be an effective treatment for rosacea and demodicosis, indirectly supporting a key role of the mite in the pathophysiology of rosacea. The two higher dose regimens were more effective than the lower dose.

Papulopustular rosacea and rosacea-like demodicosis: two phenotypes of the same disease?

BACKGROUND: Papulopustular rosacea and rosacea-like demodicosis have numerous similarities, but they are generally considered as two distinct entities, mainly because the causal role of the Demodex mite in the development of rosacea is not yet widely accepted. Several clinical characteristics are traditionally considered to differentiate the two conditions; for example, papulopustular rosacea is typically characterized by central facial papulopustules and persistent erythema, whereas small superficial papulopustules and follicular scales rather suggest rosacea-like demodicosis. However, none of these characteristics is exclusive to either entity. OBJECTIVE: To explore differences in Demodex densities according to clinical characteristics traditionally associated with these two conditions. METHODS: Retrospective, observational, case-control study of 242 patients with central face papulopustules. Demodex densities were measured on two consecutive standardized skin surface biopsies. RESULTS: In the whole cohort, Demodex densities were greater in patients with persistent erythema than in those without. In 132 patients without recent treatment or other facial dermatoses, 120 (91%) had persistent erythema, 119 (90%) small superficial papulopustules and 124 (94%) follicular scales; 116 (88%) simultaneously had clinical characteristics traditionally associated with both papulopustular rosacea and rosacea-like demodicosis. Higher Demodex densities were linked to the presence of follicular scales, but not to papulopustules size, nor to the presence/absence of persistent erythema. CONCLUSION: Our observations highlight the difficulty differentiating between these entities and suggest that rosacea-like demodicosis and papulopustular rosacea should no longer be considered as two separate entities, but rather as two phenotypes of the same disease.

Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link.

Papulopustular rosacea (PPR) is a common facial skin disease, characterized by erythema, telangiectasia, papules and pustules. Its physiopathology is still being discussed, but recently several molecular features of its inflammatory process have been identified: an overproduction of Toll-Like receptors 2, of a serine protease, and of abnormal forms of cathelicidin. The two factors which stimulate the Toll-like receptors to induce cathelicidin expression are skin infection and cutaneous barrier disruption: these two conditions are, at least theoretically, fulfilled by Demodex, which is present in high density in PPR and creates epithelial breaches by eating cells. So, the major pathogenic mechanisms of Demodex and its role in PPR are reviewed here in the context of these recent discoveries. In this review, the inflammatory process of PPR appears to be a consequence of the proliferation of Demodex, and strongly supports the hypothesis that: (1) in the first stage a specific (innate or acquired) immune defect against Demodex allows the proliferation of the mite; (2) in the second stage, probably when some mites penetrate into the dermis, the immune system is suddenly stimulated and gives rise to an exaggerated immune response against the Demodex, resulting in the papules and the pustules of the rosacea. In this context, it would be very interesting to study the immune molecular features of this first stage, named "pityriasis folliculorum", where the Demodex proliferate profusely with no, or a low immune reaction from the host: this entity appears to be a missing link in the understanding of rosacea.