Fabienne M. N. Forton

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.

Demodex folliculorum and brevis are commensal mites that live in low densities in human pilosebaceous follicles as part of the normal adult microbiota, but that give rise to demodicosis and, possibly, rosacea, when they proliferate excessively. This proliferation is favored by various factors, including age, marked immunosuppression, sebaceous gland hyperplasia, and hypervascularization‐related factors. To study possible factors influencing mite proliferation, we explored the effects of different variables on Demodex densities (Dd) in a retrospective study of two groups of subjects selected on the basis of their clinical diagnosis: Demodex+, consisting of subjects with demodicosis or with centro‐facial papulopustules suggesting rosacea (n = 844, mean Dd 263.5 ± 8.9 D/cm²), and Demodex−, consisting of subjects with other facial dermatoses or healthy facial skin (n = 200, mean Dd 2.3 ± 0.4 D/cm²). Demodex densities were measured using two consecutive standardized skin surface biopsies (SSSB1 [superficial] and SSSB2 [deep]) taken from the same facial site on each subject. In the Demodex+ group: the SSSB1 decreased with age in women (p = 0.004), and the SSSB2 increased with age in men (p = 0.001) (the pattern was similar for SSSB1 + 2, but not statistically significant); Dds were lower in those who had received cortisone (either topically or systemically); 13 subjects (1.5%) had known immunosuppression, 62 (7.3%) had hypothyroidism, and in 20 (3.6% of the women) there was a reported link with pregnancy; 78 of the subjects (9.2%) were part of a pair from the same family or household; when associated bacterial infection was suspected, Staphylococcus epidermidis was often isolated. Our results suggest close interactions between the mite, sebaceous gland size and function, and subtle variations of immune status. Potential factors influencing Demodex proliferation should be further investigated, including hypothyroidism, pregnancy, corticosteroid administration, Staphylococcus epidermidis, contagiousity, and genetic background.

Rosacea is a common facial dermatosis but its definition and classification are still unclear, especially in terms of its links with demodicosis. Triggers of rosacea (ultraviolet light, heat, spicy foods, alcohol, stress, microbes) are currently considered to induce a cascading innate and then adaptive immune response that gets out of control. Recent histological and biochemical studies support the concept that this inflammatory response is a continuum, already present from the onset of the disease, even when no clinical signs of inflammation are visible. The Demodex mite is beginning to be accepted as one of the triggers of this inflammatory cascade, and its proliferation as a marker of rosacea; moreover, the papulopustules of rosacea can be effectively treated with topical acaricidal agents. Demodex proliferation appears to be a continuum process in rosacea, and may not be clinically visible at the onset of the disease. Molecular studies suggest that Demodex may induce tolerogenic dendritic cells and collaborate with vascular endothelial growth factor (VEGF) to induce T cell exhaustion and favor its own proliferation. These interactions among VEGF, Demodex, and immunity need to be explored further and the nosology of rosacea adapted accordingly. However, treating early rosacea, with only clinically visible vascular symptoms, with an acaricide may decrease early inflammation, limit potential flare-ups following laser treatment, and prevent the ultimate development of the papulopustules of rosacea. The effectiveness of this approach needs to be confirmed by prospective controlled clinical trials with long-term follow-up. Currently, the evidence suggests that patients with only vascular symptoms of rosacea should be carefully examined for the presence of follicular scales as signs of Demodex overgrowth or pityriasis folliculorum so that these patients, at least, can be treated early with an acaricidal cream.

Background: Patients with rosacea and demodicosis have high facial skin Demodex densities (Dds), which decrease with benzyl benzoate (BB) treatment. Objectives: To evaluate the impact of topical BB (+crotamiton) treatment on Dds and clinical symptoms during prolonged follow-up and to compare low (12% once daily) and high (12% twice daily or 20-24% once daily) BB dose regimens. Methods: This retrospective study included 344 patients (103 rosacea, 241 demodicosis) observed for 7.1 ± 0.5 months. Dds were measured on two consecutive standardized skin surface biopsies and symptoms evaluated using investigator global assessment. Compliance was considered good if patients correctly followed treatment instructions. Results: At final follow-up, in the 248 patients with good compliance, Demodex density had normalized in 217 (88%) and symptoms cleared in 204 (82%). The high dose was associated with better compliance and faster results than the low-dose. The higher the initial Dd, the longer it took to normalize. In the 96 poorly compliant patients, treatment was less effective and slower. Conclusion: These findings indirectly support a key role of the mite in rosacea and suggest that topical treatment with BB (+crotamiton), especially the higher dose, may be a useful alternative treatment for rosacea as well as for demodicosis.

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.

Background Facial densities of Demodex mite have been observed to be greater in patients with demodicosis and papulopustular rosacea than in healthy control patients. In patients with erythematotelangiectatic rosacea (ETR), this density has been observed to be similar to or greater than that of healthy controls. Erythema and telangiectasia, characteristics of ETR, are often observed among patients with pityriasis folliculorum, a discreet demodicosis, suggesting a possible link between these conditions. Objectives To compare the facial Demodex densities of patients with clinical ETR and patients with healthy skin, demodicosis, rosacea with papulopustules, and other dermatoses. Methods In this retrospective study, we recorded Demodex densities measured using two consecutive standardised skin biopsies (SSSB1 and SSSB2) in 23 patients with ETR, 20 healthy control patients, 590 patients with demodicosis, 254 with rosacea with papulopustules, and 180 with other facial dermatoses. Results Patients with ETR had higher Demodex densities than did the healthy controls (mean ±SEM, SSSB1: 15.7±6.3 vs. 1.8±1.1 Demodex(D)/cm² [p=0.042]; SSSB2: 38.0±13.7 vs. 5.1±2.1 D/cm² [p=0.026]) and patients with other dermatoses (SSSB1: 0.4±0.1D/cm² [p=0.004]; SSSB2: 1.3±0.3 D/cm² [p=0.004]), but lower than patients with demodicosis (SSSB1: 82.7±4.2D/cm² [p=0.008]; SSSB2: 172.2±7.7 D/cm² [p=0.001]) or rosacea with papulopustules (SSSB1: 86.6±7.3 D/cm² [p=0.027]; SSSB2: 197.0±12.1 D/cm² [p=0.002]). Conclusions ETR may be associated with non‐visible Demodex proliferation, possibly corresponding to a subclinical stage of demodicosis. Dermatologists should be aware of this potential association and look for subclinical demodicosis in patients with ETR, so that topical acaricidal treatment can be offered if Demodex density is high.

Linked article: This article is commented on by A.L. Tatu et al., pp. e46–e47 in this issue. To view this article visit https://doi.org/10.1111/jdv.15166

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 and demodicosis are characterized by non-specific symptoms, which can make cl...