Article

Demodex mites modulate sebocyte immune reaction: Possible role in the pathogenesis of rosacea

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Abstract

Rosacea is a common facial skin disorder affecting middle‐aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as important. The Demodex mite population in the skin of these patients is significantly higher than in subjects with normal skin suggesting they may be of etiological importance in this disorder. Little is known of the role of these mites in human skin and their potential to interact with the host immune system has not been elucidated. Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalised SZ95 sebocyte line. Time and mite dose dependent experiments were performed. Direct Demodex effects and the effects of medium in which Demodex had been cultured were evaluated on the TLR‐signalling pathway on both a gene and protein expression level. Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards down modulation of genes in this pathway was observed. A subsequent switch to positive gene up‐regulation was recorded after 48 hours of co‐culture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced pro‐inflammatory cytokine secretion whereas lower numbers did not. Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalised human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced IL8 secretion by these cells. This article is protected by copyright. All rights reserved.

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... Humans are born without Demodex mites on the skin [43,54], and the mites are progressively acquired by direct contact with the skin of other humans [44,55]. As a commensal, the Demodex mite likely controls the immune system of the host, through undefined mechanisms, to ensure its own survival [8,10,[56][57][58][59][60]. ...
... While it likely induces immunotolerance, Demodex is also able to stimulate the immune system's defense reaction [34, 43,57,58,104,110]. It stimulates Toll-like receptor 2 (TLR2) [58], resulting in an increased production of LL-37, with the subsequent angiogenesis and inflammation that are described in rosacea [15][16][17][18]. ...
... While it likely induces immunotolerance, Demodex is also able to stimulate the immune system's defense reaction [34, 43,57,58,104,110]. It stimulates Toll-like receptor 2 (TLR2) [58], resulting in an increased production of LL-37, with the subsequent angiogenesis and inflammation that are described in rosacea [15][16][17][18]. This implies the existence of a vicious circle including ETR, mite proliferation, and inflammation [10]. ...
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Article
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 inflam-matory 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 rosa-cea; 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 vas-cular symptoms of rosacea should be carefully examined for the presence of follicular scales as signs of Demodex overgrowth or pityriasis fol-liculorum so that these patients, at least, can be treated early with an acaricidal cream.
... 95,96 Stimulation of humoral immunity by the mites has also been recorded, 97,98 and stimulation of sebocyte TLR2 and inflammatory cytokines by large numbers of D. folliculorum was recently demonstrated in an in vitro study. 99 Mast cells play a crucial role in the inflammatory cascade associated with rosacea, 19,26,100 by releasing vascular endothelial growth factor (VEGF), histamine, proteases and factors causing dermal fibrosis [tryptase, matrix metalloproteases (MMPs) and transforming growth factor bêta-1 (TGF-b1)] 20,26,100-102 leading to phymatous changes. This effect may explain why Demodex can induce fibrosis (as suggested by histological observations) 76 from the early stages of rosacea 26 and why this fibrosis is so important in rhinophyma, if we consider that the density of pilosebaceous follicles is highest on the nose 103 and the frequent presence of Demodex mites in phyma biopsies. ...
... In small quantities, they down-regulate the TLR2 response of sebocytes, and in large quantities they stimulate IL-10 production. 99 The mechanisms by which Demodex controls host immunity are not yet fully understood: the mite may block certain molecules that are necessary for an effective anti-parasite immune response (e.g. STAT1, STAT6 and CD28) 106,125,127,128 ; it may also induce immunotolerance via its Thomsen nouveau (Tn) Ag, 131 as I recently suggested. ...
... 10,172 This is explained by the immunosuppressive action of the mite on the immune response which may surpass its immunogenic action (see rebuttal to argument 2; Fig. 2). 33,99,129,130 In 1976, Rothman proposed a model centred on the multicausality of chronic diseases, based on the notions of sufficient Table 2 Hill's epidemiologic criteria for causal association applied to Demodex and rosacea with papulopustules (PPR) ...
Article
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, 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 favoring 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 (VEGF), which may also explain the favorable 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, Rothman model). The findings suggest that PPR can reasonably be attributed to Demodex proliferation, which appears to be a necessary factor in the center 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.
... Live Demodex mites obtained from normal facial skin of human subjects were shown to exert immunomodulatory effects on immortalized human sebaceous gland cell line, via secreted bioactive molecules that influences Toll-like receptor (TLR)-2 expression (58). The immunomodulatory activity was time-and mite number-dependent since suppression of cytokine production was reversed, and secretion of pro-inflammatory mediators was initiated after 48 hours of challenge or when high number of mites were used for in vitro stimulation (58). In the same study, while significantly upregulated levels of TNF-α production was detected after 8 hours of treatment of cells with Demodex mites, no significant differences were found when compared with untreated cells by the end of 48-hour incubation period. ...
... Additionally, in an attempt to further characterize the immune response generated, flow-cytometric analysis of whole blood samples collected from human demodicosis and healthy subjects revealed that primary demodicosis group patients displayed higher T H 9 and T reg cell levels in total blood and skin-homing T-cell populations than control subjects (70). In support for T reg cell role in human demodicosis, sebocytes upon challenge with Demodex mites were reported to release IL-10, a cytokine associated with T reg responses (58). ...
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Article
Demodex mites are saprophytic parasites of the mammalian skin, mostly found in or near pilo‐sebaceous units of hairy regions. While they can be found in healthy humans and animals without causing any clinical manifestations, they were suggested to create pathogenic symptoms when they appear in high densities under favourable conditions (i.e. demodicosis). Nevertheless, their role as the primary causative agent of the pathogenic conditions in humans is debated today. Canine demodicosis, which is highly prevalent in certain dog breeds, provides a valuable tool for studying the pathogenesis of human demodicosis. Canine and human demodicosis are caused by different Demodex species, and the clinical manifestations in former could be life‐threatening. Nevertheless, current literature suggests similar immune responses and immune evasion mechanisms in human and canine demodicosis; cellular immunity appeared to have a central role in protection against demodicosis, and Demodex mites were shown to influence both innate and adaptive immune response to escape immune attack. The aim of this review is to summarize the relevant literature on demodicosis obtained from studies conducted on both organisms, and draw the attention to the effect of mite‐associated factors (e.g. microbiota) on the different clinical manifestations displayed during human and canine demodicosis.
... [2][3][4] The data on their biological function and pathogenic potential are scarce. 1,5 The Demodex parasites' density is considered the key issue for the emergence of clinical manifestations. [6][7][8] In addition to primary cutaneous demodicosis, several reports defined the successful treatment outcomes of numerous topical and systemic anti-Demodex agents, particularly for rosacea, perioral dermatitis, and targeted chemotherapy-related papulopustular eruptions. ...
... [6][7][8] In addition to primary cutaneous demodicosis, several reports defined the successful treatment outcomes of numerous topical and systemic anti-Demodex agents, particularly for rosacea, perioral dermatitis, and targeted chemotherapy-related papulopustular eruptions. 5,[8][9][10] Due to the relatively bigger size of these mites, in vitro Demodex killing activity of potential therapeutic agents can be evaluated practically by observing the parasites' movements and integrity upon exposure to these agents. 11,12 Besides, Demodex mites can be easily isolated by minimally invasive methods among routine clinical practice. ...
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Article
Background Demodex mites have been implicated in several cutaneous disorders compelling the research efforts for effective anti-Demodex therapy. Objective Compare the survival time (ST) of Demodex folliculorum exposed to six different concentrations of tea tree oil (TTO) versus a positive control (permethrin 5%) and a negative control (immersion oil) group. Materials and methods The wastes of rosacea patients’ standardized superficial skin biopsy samples were recruited for the trial. The primary outcome measure of this study was the survival time, defined as the period between the exposure of study agents to the complete cessation of Demodex movements. Results All differences between the mean survival times of 2.5% (54.0 ± 6.1), 5% (39.0 ± 3.9), 10% (22.0 ± 2.5), 25% (13.0 ± 2.5), 50% (7.8 ± 0.6), and 100% TTO (3.3 ± 1.3) were significant (p < 0.05). The ST of the negative control group was 196.0 ± 23.6 min. The ST of permethrin 5% was 12.5 ± 1.9 that did not show a statistically significant difference from the ST of TTO 25% (p = 0.628). Conclusion The survival times of the six different TTO groups confirmed a dose-related pattern, all of which had survival times shorter than the negative control (immersion oil). TTO 25% had comparable efficacy to the positive control agent (permethrin 5%).
... 8,10 It has also been documented that infants may become infected by contact with colonized mothers skin. 12,13 Therefore, Demodex mites have a cosmopolitan distribution and are found in about 10% of biopsy specimens of healthy human skin, where they are present in about 12% of all follicles. Various studies have shown normal rates of colonization to be 20% to 80%. ...
... Various studies have shown normal rates of colonization to be 20% to 80%. 12,13 The prevalence of both Demodex species increases with the host age and in adults reaches even 100% with a density of more than 5 mites per 1 cm 2 of normal skin. 14,15 Usually the Demodex infection in humans occurs asymptomatically. ...
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Article
Introduction: Demodex mites are associated with various symptoms pertaining to facial and eyelid skin in humans. Demodicosis is often reported in elderly people, above 50 years of age. In young adults, the Demodex spp. infection is less common and is asymptomatic or the symptoms are mild. Aim: The aim was to evaluate the occurrence of Demodex spp. in healthy young adults in Poland and analyze the associations between the presence of mites, participants gender and skin type, with regards to hygienic practices and symptoms. Material and methods: The content of facial sebaceous glands and eyelash follicles was examined in a group of 94 people, aged 18–32 years. Metric data and information about face and eyelid skin symptom occurrence, skin type and hygienic practices were collected by diagnostic survey. Results and discussion: Demodex spp. was identified in 21.3% of subjects. In 45% and 30% of carriers Demodex folliculorum and Demodex brevis occurred, respectively. A mixed infestation in 25% of subjects was detected. Demodex infestation was slightly higher in people with oily and mixed skin (23.5%), compared to those with dry and normal skin (18.6%). No significant influence of shared hygienic accessories on the level of Demodex spp. infection were observed. The skin symptoms of the face and eyelids were reported at 75% for subjects positive for Demodex. Conclusions: Demodex mites are often prevalent in healthy young adults in Poland in both the sebaceous glands of the face and hair follicles. While diagnosing face and eyelid skin diseases in young people, Demodex spp. infection should be considered.
... Increased proliferation of Demodex has been associated with the impaired immune status of the host and/or immune response to the mite (3). It has also been suggested that these mites can both create a suitable environment for mite proliferation by showing immunosuppressive effects on the skin and preparing the ground for secondary infections on the skin (3,4). The link between the presence of the mites and the activation of inflammatory pathways is unclear, as the potential of Demodex mites to influence cellular immune-mediated responses has not been fully defined (4) Despite this uncertainty, demodicosis, which is usually asymptomatic, is known to cause some skin diseases as a result of an imbalance in immune system mechanisms (5). ...
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Article
Objective: Demodex folliculorum and Demodex brevis are two species known to settle on the skin of humans. Demodex mite infections are called demodicosis. Demodicosis, which is usually asymptomatic, is known to cause some skin diseases as a result of an imbalance in immune system mechanisms This study was conducted to investigate the relationship between Demodex spp. infestations and clinical signs, such as immunodeficiency, rosacea, blepharitis and facial itching, facial flushing, facial tenderness, facial rash, and sunburn. Methods: A total of 350 patients, 178 of whom were immunosuppressed and 172 who were immunocompetent, were included in the study. Samples were taken from the nose, chin, and forehead areas, using the standard superficial skin biopsy method and were examined under a microscope. Results: Demodex spp. was detected in 224 of the 350 patients, including 144 (80.90%) of the 178 immunosuppressed patients and 88 (51.16%) of the 172 immunocompetent patients included in the study. The difference between Demodex spp. positivity in the immunosuppressed patients and positivity in the immunocompetent patients was statistically significant. In addition, a relationship was found between Demodex spp. and some clinical symptoms. Conclusion: Demodex spp. proceed a health problem in rosacea and immunosuppressed patients. It was concluded that Demodex spp. should definitely be considered in cases of facial sensitivity, facial rash, and facial flushing in both immunosuppressed and immunocompetent patients, especially in the presence of sunburn in immunosuppressed patients, which was revealed by this study.
... Although a pathophysiological role of the Demodex mite is generally accepted in demodicosis, it remains controversial in rosacea with papulopustules (4,5). Nevertheless, evidence is accumulating to support a key role of the mite in this condition, including the high mean Demodex densities (Dds) consistently observed in rosacea with papulopustules (6)(7)(8)(9)(10)(11)(12)(13), the ability of the mite to induce both immunosuppression (favoring its own proliferation) and immunostimulation (inducing inflammation and papulopustules) (9,(13)(14)(15)(16)(17), and the beneficial effects of topical acaricidal treatment in patients with rosacea with papulopustules (18)(19)(20)(21)(22)(23)(24)(25)(26). Moreover, recent guidelines for the treatment of rosacea include use of ivermectin, an acaricidal agent, as a first line topical treatment for rosacea with papulopustules (19)(20)(21)(22)(23). ...
Article
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.
... It is often painless and easily tolerated by the patient, even if the sample is removed from the contents of the upper pilosebaceous canals. 1,5,32,33 Likewise, in our study, we examined the skin by using SSSB to determine the number of mites/cm 2 ( Table 1). Demodex mite presence was higher in RA patients than in healthy controls. ...
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Objectives: This study aims to investigate the presence of Demodex species in rheumatoid arthritis (RA) patients, to identify the risk factors for developing Demodex infestation, and to determine the effect of immunosuppressant drugs on Demodex mite infestations. Patients and methods: The study included 93 RA patients (16 males, 77 females; mean age 53.3±11.3 years; range, 27 to 83 years) and 76 healthy controls (19 males, 57 females; mean age 50.3±13.9 years; range, 19 to 86 years). Specimens were collected from face skin by using standardized sur- face skin biopsy. Demodex infestation was considered for ≥5 living parasites/cm2 of skin while Demodex mite presence was defined as any Demodex larvae, adults, or eggs found in the specimen. Results: The frequencies of Demodex mite presence were 44% for the RA patients and 15.7% for the healthy controls (p<0.001). The rates of Demodex infestation were similar between the two groups (18.3% versus 7.9%, p=0.054). There were no statistically significant differences between the groups regarding skin type, skin care, epilation, body washing, use of a moisturizer, personal towel use, the number of residents at home, or whether there were pets at home or in proximity. Itching in eyes was higher in RA patients, but the frequency of other skin symptoms was not differ- ent from healthy controls. Logistic regression analysis indicated that the diagnosis of RA was an independent risk factor for Demodex mite presence in this study population. Disease activity and duration, use of corticosteroids, conventional disease-modifying anti-rheumatic drugs (DMARDs) and biological DMARDs were not effective factors on Demodex mite presence in RA patients. Conclusion: Although Demodex mite presence was 3.5-fold higher in RA patients, the rate of Demodex infestation was similar to that of healthy controls.
... Interestingly, both MAPK and TNF signaling pathways have also been associated with ocular rosacea (Wladis et al., 2019(Wladis et al., , 2017, suggesting a shared mechanism between PPR and ocular rosacea. Furthermore, the TNF signaling pathway can also be triggered by the activation of toll-like receptor 2 with Demodex mites, a known external stimulus of rosacea (Lacey et al., 2018), and toll-like receptor upregulation has been previously described for rosacea (Buhl et al., 2015). ...
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Article
Papulopustular rosacea (PPR) is a chronic inflammatory skin disease with limited treatment options. Although multiple pathways have been described to be upregulated in PPR, a mechanistic understanding of the key drivers and interaction between pathways in PPR pathology is lacking. In this study, we utilized PPR biopsy explants to integrate both differentially expressed genes (DEGs) and differently expressed proteins (DEPs) in paired non-lesional (NL) and lesional (LS) PPR tissue (n=5 patients). The results of this study identified 92 DEGs and 20 DEPs between paired PPR LS and NL explants. MAPK and TNF signaling pathways were the most significantly upregulated pathways in PPR LS tissue and aligned with DEPs identified in this study. Both MAPK and TNF signaling pathways highlighted IL-1β as a potential central mediator to PPR pathogenesis. In support of this, stimulation of NL explants with IL-1β resulted in a transcriptomic and proteomic profile similar to LS PPR. In this integrative transcriptomic and quantitative protein analysis, we identified several inflammatory genes, proteins, and pathways which may be contributing to PPR, as well as highlighted a potential role of IL-1β in driving inflammation in PPR.
... LY96 enhances TLR2, TLR4 and the NF-κB signal transduction pathway [35]. A recent study showed that Demodex mite extracts decreased TLR2 expression in cultured sebocytes [36], although this may be mite density dependent, as higher mite numbers appear to be associated with activation of TLR inflammatory pathways and rosacea pathogenesis. Factors affecting this "switch" from TLR mediated immune modulation to stimulation are not clear [37]. ...
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Article
Scabies is a neglected tropical disease of global significance. Our understanding of host-parasite interactions has been limited, particularly in crusted scabies (CS), a severe clinical manifestation involving hyper-infestation of Sarcoptes scabiei mites. Susceptibility to CS may be associated with immunosuppressive conditions but CS has also been seen in cases with no identifiable risk factor or immune deficit. Due to ethical and logistical difficulties with undertaking research on clinical patients with CS, we adopted a porcine model which parallels human clinical manifestations. Transcriptomic analysis using microarrays was used to explore scabies pathogenesis, and to identify early events differentiating pigs with ordinary (OS) and crusted scabies. Pigs with OS (n = 4), CS (n = 4) and non-infested controls (n = 4) were compared at pre-infestation, weeks 1, 2, 4 and 8 post-infestation. In CS relative to OS, there were numerous differentially expressed genes including pro-inflammatory cytokines (IL17A, IL8, IL19, IL20 and OSM) and chemokines involved in immune cell activation and recruitment (CCL20, CCL27 and CXCL6). The influence of genes associated with immune regulation (CD274/PD-L1 and IL27), immune signalling (TLR2, TLR8) and antigen presentation (RFX5, HLA-5 and HLA-DOB) were highlighted in the early host response to CS. We observed similarities with gene expression profiles associated with psoriasis and atopic dermatitis and confirmed previous observations of Th2/17 pronounced responses in CS. This is the first comprehensive study describing transcriptional changes associated with the development of CS and significantly, the distinction between OS and CS. This provides a basis for clinical follow-up studies, potentially identifying new control strategies for this severely debilitating disease.
... Mites may incite hypersensitivity reaction in younger people and as age advances, immunity fades and the mites just colonize and survive in harmony. [21][22][23] Presence of CDs increases the yield of Demodex. [11] In the study conducted by Kheirkhah et al., equal number of patients had diffuse and sporadic CDs. ...
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Article
Purpose: To report clinical characteristics of Demodex blepharokeratoconjunctivitis affecting young patients. Methods: This is a retrospective review of 14 patients with the history of chronic red eyes with corneal involvement. All patients were diagnosed with ocular demodicosis based on the results of eyelash sampling. All patients were treated with 50% tea tree oil lid scrubs and two doses of oral ivermectin (200 mcg/kg). Results: The median age of patients at diagnosis was 27 years (range: 11-39 years). The duration of symptoms ranged from 2 months to 20 years. Rosacea was present in only three patients. Four patients had best corrected visual acuity less than 20/60. Allergic conjunctivitis (n = 7) and viral keratitis (n = 5) were the most common misdiagnosis previously made. Cylindrical dandruff was present in only six patients and eyelashes were clean in rest of them. Inferior vascularization was present in eight eyes, superior in seven eyes, and corneal scars were present in 12 eyes. Four patients had steroid-related complications. All patients, except one responded to tea tree oil treatment and 13 patients were off steroids after 3 weeks of starting the treatment. Conclusion: Demodex infestation of eyelids can lead to chronic blepharokeratoconjunctivitis in healthy pediatric and young adult patients who otherwise have good hygiene, which can often be overlooked or misdiagnosed. Viral keratitis and allergic conjunctivitis are common misdiagnoses and demodicosis can be confirmed by simple epilation. Early diagnosis and treatment can prevent long-term steroid use and its related complications.
... In addition, significant correlation was found between facial rosacea, eyelid inflammation and Demodex eye infestation with serum immunoreactivity to Bacillus proteins [24,25]. Demodex mites are believed to induce acute blepharitis and conjunctivitis (thereby inducing inflammation) by causing skin disruption [26], immune evasion [27,28] and bacterial (i.e., staphylococci and sterptococci) transfer [29,30]. In addition, D. brevis can physically block the meibomian gland, inducing chalazion (a lump in the eyelid caused by obstruction and inflammation of the meibomian gland), glandular inflammation, and tear lipid paucity [19,31]. ...
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Article
Rosacea is a facial inflammatory dermatosis that is linked with various systemic illnesses. With regards to the eye, rosacea patients have been described to manifest ocular surface changes, such as blepharitis and conjunctivitis. However, studies that examine the association of rosacea with a wider array of ocular diseases are limited. Thus, our aim was to identify the range of ocular comorbidities in the Korean patient population and create a reference data set. A multi-institutional, case-control study was conducted, where 12,936 rosacea patients and an equal number of sex- and age-matched control subjects were extracted over a 12-year period. We were able to discover a notable association between rosacea and blepharitis (adjusted odds ratio (aOR) 3.44; 95% confidence interval, 2.71–4.36, p < 0.001), conjunctivitis (aOR 1.65; 95% CI, 1.50–1.82, p < 0.001), glaucoma (aOR 1.93; 95% CI, 1.70–2.20, p < 0.001), dry eye syndrome (aOR 1.89; 95% CI, 1.70–2.09, p < 0.001), and chalazion (aOR 3.26; 95% CI, 1.41–7.57, p = 0.006) from logistic regression analysis. Female subjects and individuals younger than 50 exclusively showed higher odds for chalazion. Our study suggests that ocular comorbidities (i.e., glaucoma, dry eye syndrome, and chalazion as well as blepharitis and conjunctivitis) are more prevalent among Koreans with rosacea. Clinicians should proactively check ocular symptoms in rosacea and employ joint care with an ophthalmologist in cases of need.
... In this study, infested sheep showed significantly higher IFN-c and TNF-a levels than that in non-infested sheep. These results agree with that recorded in different parasitic infections as (Toxoplasma gondii; Neospora caninum; Demodex mites and malaria infection) by Donahoe et al. 2017;Lacey et al. 2018 andNasr et al. 2014 which recorded significant high IFN-c and TNF-a levels. This data was considered as a beginning of further researches on the functional and genetic analysis of the TNF-a and IFN-c genomic region in the oestrosis infestation of sheep. ...
Article
This study aimed to evaluate the cell mediated immune responses against Oestrus ovis (O. ovis) in sheep through measurement of the changes in mRNA expression of the tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) cytokines using quantitative Real time-PCR (qRt-PCR). Also; to detect the role of Oestrus ovis infestation in the oxidative stress markers in sheep. Fifty sheep head were examined in Cairo abattoir from the period of May to August 2019. Sera were separated and collected for measurement of nitric oxide, zinc and malondialdehyde (MDA). While TNF-α and IFN-γ mRNA were extracted from nasal mucosa. Levels of IFN-γ and TNF-α were significantly higher in infested sheep than that in non-infested one. Also, oxidative stresses were indicated by high level of nitric oxide as one of reactive oxygen species (ROS) and serum MDA as oxidative stress marker and low antioxidant capacity (zinc concentration in serum) in infested sheep. The obtained results indicated that measurements of TNF-α and IFN-γ cytokines using qRT-PCR could be used as an association and reproducible quantitative method for the diagnosis of O. ovis infestation in sheep.
... 4 In a study, authors suggested that increased Demodex mite numbers in the facial skin might be a trigger on the immune reaction leading to inflammatory skin changes by activation of the toll-like receptor 2 (TLR2) pathway response. 5 Identification of the endobacterium (Corynebacterium kroppenstedtii subsp. demodicis) of Demodex follicularum may be the starting point for understanding the interaction between demodex mites, bacterial endosymbiont and human host. ...
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Article
Discoid lupus erythematosus (DLE) is a chronic inflammatory erythematous skin disease that can be triggered by several factors. Rosacea is another skin disease that causes facial redness and tenderness. Demodex mites have been reported in rosacea and DLE patients commonly in the literature. These two diseases can be seen concomitant, mimic each other clinically and share common possible etiologic factors. To assess Demodex mite infestation in both clinical and histopathological findings in DLE patients. We retrospectively evaluated the files of 42 patients with DLE who had been diagnosed DLE based on clinical and histopathological findings between August 2018 and August 2019. Demodex positivity was detected 50% of patients (n = 21). Neutrophile percentages in the dermal and perivascular area were higher in the demodex positive patients (4,43%) than in the Demodex negative patients (2,19%). The intensity of demodex mites correlated positively with dermal neutrophile percentages. ANA was negative in 29 patients (69%) and positive in 13 patients (31%). Anti‐dsDNA was negative in serology and follicular plugging was positive in histopathology in all 42 patients (100%). This was a retrospective study. DLE and rosacea share common features in etiopathogenesis and clinical presentation. Inflammation and exacerbations caused by the demodex mites may increase the clinical severity of DLE. Although the position of demodex mites in DLE etiopathogenesis is not known exactly, the presence of high demodex in DLE patients has been determined. Standard skin surface biopsy can be a routine procedure for the evaluation of DLE patients in daily clinical practice. This article is protected by copyright. All rights reserved.
... Rosacea is a chronic inflammatory skin disorder of uncertain etiology, characterized by among others papules, pustules, erythema, telangiectasia, and flushing (14)(15)(16). Demodex mites have been implicated in rosacea etiology (14,(17)(18)(19), and studies show that the Demodex population is markedly increased in patients with rosacea compared to healthy controls (20)(21)(22)(23)(24)(25). ...
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Background: Reflectance confocal microscopy (RCM) enables noninvasive Demodex mite detection in rosacea. Objective scoring of rosacea severity is currently lacking. Objectives: To determine the value of RCM for monitoring Demodex, inflammation and vascular parameters in rosacea during treatment. Methods: In 20 rosacea patients, clinical and RCM examination were performed before, during, and 12 weeks after a 16-week treatment course with topical ivermectin. Using RCM, number of mites and inflammatory cells, epidermal thickness, and vascular density and diameter were measured. RCM features were correlated with clinical assessment. Results: Treatment resulted in clinical reduction of inflammatory lesions. Mites were detected in 80% of patients at baseline, 30% at week 16, and 63% at week 28. The number of mites reduced significantly during treatment, but no changes in inflammatory cells, epidermal thickness or vascular parameters were observed. Correlation between number of inflammatory lesions and mites was low. None of the RCM variables were significant predictors for clinical success. Conclusions: RCM enables anti-inflammatory effect monitoring of topical ivermectin by determining mite presence. Quantifying exact mite number, and inflammatory and vascular characteristics is challenging due to device limitations. In its current form, RCM seems of limited value for noninvasive follow-up of rosacea in clinical practice.
... It has been proposed as a vascular lability disease, as a dysfunction of the immune system, with a genetic influence or a hypersensitivity reaction to Demodex folliculorum. 17 Most of the biopsies showed features of inflammation and vascular dysfunction, highly suggestive of a rosacea histological picture complicated by chronic lymphoedema. The presence of the latter clearly suggests a vascular channel insult. ...
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Purpose: To describe 10 patients with Morbihan syndrome, a rare condition characterized by the slow appearance of erythema and solid edema on the upper portion of the face, and review the literature. Methods: Retrospective case series and review. Results: The majority of patients were male (80%), and the mean age at presentation was 67 years (range, 48-88 years); 60% had asymmetrical disease (affecting mainly the right side). All subjects underwent a lid biopsy to support the diagnosis of Morbihan syndrome, which showed features of inflammation and vascular dysfunction, highly suggestive of a rosacea histological picture complicated by chronic lymphoedema. A range of medical and surgical treatment were used with variable success. The most effective ones included oral isotretinoin, intralesional triamcinolone injections, and debulking surgery. Conclusions: Morbihan syndrome is a rare and chronic condition. It can be difficult to treat and may require a range of interventions.
... This is surprising, as many questions about these mites remain elusive: they cannot be cultivated ex-vivo, their pathomechanism is largely unknown, and their position as a commensal (and facultatively pathogenic parasite) is uncertain (Chen and Plewig 2015), as they can modulate the host's immune system (Lacey et al. 2018) and might defend their niche habitats against bacteria and fungi. ...
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Demodex spp. mites are the most complex organisms of the human skin microbiome and were discovered more than 175 years ago, yet only little basic research is published about them. As they can be pathophysiologically relevant ectoparasites associated with rosacea, pityriasis folliculorum, and other inflammatory skin diseases, more research should be encouraged. Being a large microorganism or a tiny animal, there are no established basic methods to handle these mites. Here, we describe techniques enabling the extraction of Demodex mites from human skin, their analysis in different ex-vivo settings, the lysis of their exoskeleton, their preservation by freezing, and observation microscopically using specific fluorescent dyes or their inherent autofluorescence. These procedures should facilitate future Demodex research and fuel further the generation of knowledge. Furthermore it is intended to ultimatively enable the mite's cultivation in vitro and reveal its pathophysiological mechanisms.
... An immune defect against Demodex is believed to enable proliferation of the mite, which penetrates the dermis and activates Toll-like receptor 2 (TLR2), leading to inflammation. 9,14 Demodicosis has been described previously in only one family with STAT1-GOF mutation. 6 The exact mechanism causing demodicosis in patients with STAT1-GOF mutations is unknown. ...
Article
Heterozygous STAT1 gain‐of‐function (GOF) mutations result in a combined form of immunodeficiency which is the most common genetic cause of chronic mucocutaneous candidiasis (CMC). We present a pedigree with a GOF mutation in STAT1, manifesting with chronic demodicosis in the form of a facial papulopustular eruption, blepharitis, and chalazion. So far, demodicosis has been described in only one family with STAT1‐GOF mutation. We suggest that chronic demodicosis is an under‐recognized feature of the immune dysregulation disorder caused by STAT1 gain‐of‐function mutations.
... Concerning the type of lesions, 87.5% of D+ patients presented a combination of erythema and papulopustules. In fact, these mites may induce a vasodilation that favors their proliferation, resulting in an inflammatory reaction and vasodilation (Casas et al., 2012;Forton, 2012;Lacey, Russell-Hallinan, Zouboulis, & Powell, 2018). ...
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Background: Ivermectin is a drug approved for the treatment of papulopustular rosacea. Although clinical guidelines recommend the use of ivermectin as the first-line treatment in patients with almost clear and mild rosacea, studies concerning its use on them are lacking. Objective: This study investigated the effectiveness and the tolerability of ivermectin in almost clear to severe rosacea and assessed the anti-parasitic effect on Demodex mites. Methods: This is a retrospective study based on 50 patients affected by papulopustular rosacea and treated with topical ivermectin 1% once daily over 16 weeks. The disease severity, the patient-examined improvement and the safety assessment of patients were evaluated. Demodex mites were studied with the standardized skin surface biopsy. Results: Papulopustular rosacea to all severity achieved a therapeutic success. The number of inflammatory lesions was significantly decreased in almost clear (P<0.0001), mild, moderate and severe (P<0.001) forms. A complete remission of inflammatory lesions was achieved by almost clear (p<0,001) and mild (p=0,005) with 82% with none-to-mild cutaneous adverse events. Thirty-two percent were positive for Demodex mites and all of them turned negative after 16 weeks. Conclusion: Ivermectin is an effective treatment not only in moderate-severe papulopustular rosacea but also in almost clear/mild rosacea. This article is protected by copyright. All rights reserved.
... It has also been suggested that these mites can both create a suitable environment for mite proliferation by showing immunosuppressive effects on the skin and preparing the ground for secondary infections on the skin (3,4). The link between the presence of the mites and the activation of inflammatory pathways is unclear, as the potential of Demodex mites to influence cellular immune-mediated responses has not been fully defined (4) Despite this uncertainty, demodicosis, which is usually asymptomatic, is known to cause some skin diseases as a result of an imbalance in immune system mechanisms (5). ...
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Objective: Demodex mites are microscopic arthropods that live on the skin of mammals and are obligate parasites. Demodex folliculorum and Demodex brevis are two species known to settle on the skin of humans. Demodex mite infections are called demodicosis. Demodicosis, which is usually asymptomatic, is known to cause some skin diseases as a result of an imbalance in immune system mechanisms This study was conducted to investigate the relationship between Demodex spp. infestations and clinical signs, such as immunodeficiency, rosacea, blepharitis and facial itching, facial flushing, facial tenderness, facial rash, and sunburn. Methods: A total of 350 patients, 178 of whom were immunosuppressed and 172 who were immunocompetent, were included in the study. Samples were taken from the nose, chin, and forehead areas, using the standard superficial skin biopsy method and were examined under a microscope. Results: Demodex spp. was detected in 224 of the 350 patients, including 144 (80.90%) of the 178 immunosuppressed patients and 88 (51.16%) of the 172 immunocompetent patients included in the study. The difference between Demodex spp. positivity in the immunosuppressed patients and positivity in the immunocompetent patients was statistically significant. In addition, a relationship was found between Demodex spp. and some clinical symptoms. Conclusions: Demodex spp. remains a health problem in rosacea and immunosuppressed patients. It was concluded that Demodex spp. should definitely be considered in cases of facial sensitivity, facial rash, and facial flushing in both immunosuppressed and immunocompetent patients, especially in the presence of sunburn in immunosuppressed patients, which was revealed by this study.
... According to the scientific organization of the European Dermatological Forum, the disease of demodicosis can go into acne. Given the localization of rashes on the face in almost all patients, there is no doubt that acne and demodicosis have an effect on their psycho-emotional state [4][5][6]. Thus, the pronounced impact of the disease on the psycho-emotional sphere and social adaptation of patients determine the urgency of this problem and the need to develop new effective treatments. In this regard, the development of drugs for local therapy of this disease is an urgent medical and pharmaceutical task. ...
Article
Objective: The aim: To conduct a marketing audit of the pharmaceutical market of Ukraine for acne and demodicosis medications. Patients and methods: Materials and methods: The study used marketing methods of analysis, survey, observation methods and reference literature - State Register of Medicines of Ukraine of the State Expert Center of the Ministry of Health of Ukraine. Results: Results: As a result of marketing audit of retail audit data of pharmacy sales revealed that the leading sales in packaging is MNL benzylbenzoate, the share of which reached in different years from 45% to 32%, which was 1380902 and 647576 packages per year, respectively, in second place - metronidazole , benzoyl peroxide, zinc ointment and sulfur ointment respectively. Conclusion: Conclusions: According to our analysis, it has been found that the highest sales volume (in packs) are of the low-cost brands, which are the most economically available and have the most effective therapeutic effect. Therefore, it is important to create multicomponent soft drugs in the form of cream and gel based on metronidazole, benzyl benzoate and benzoyl peroxide.
... 12 One theory regards Demodex mites as a vector carrying bacteria to produce superantigens, cause mechanical obstruction in follicles, and activate the Toll-like receptor 2 (TLR2). 9 Thus, the innate immune response is enhanced to produce more pro-inflammatory mediators, such as IL-8, and IL-12p70 to activate CD4 + T helper cells and macrophages and foster Langerhans-cell infiltration. 9 T4O possesses anti-parasitic, and anti-inflammatory properties by suppressing superoxide production and pro-inflammatory cytokines which may also explain the rapid resolution of symptoms in this case. ...
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Purpose To report a successful treatment of chronic rosacea associated ocular demodicosis with lid scrub containing terpinen-4-ol (T4O). Observations A 72-year old woman presented with recurrent and refractory ocular erythema, irritation, dryness, and photophobia despite conventional medical treatment (artificial tears, hypochlorous acid lid hygiene, doxycycline, and erythromycin) for 5 years. Examination revealed facial erythema, telangiectasias on cheeks, nose and lids, and cylindrical dandruff (CD) on bilateral upper and lower lashes. Epilation sampling confirmed demodicosis. After treatment with lid wipe containing T4O (Cliradex, Biotissue, Miami, FL) over face and lids, ocular discomfort, CD, facial and eyelid erythema, telangiectatic vessels were significantly reduced. Complete eradication of demodex mites and resolution of symptoms and signs lasted 8 months of follow-up. Conclusions This case suggests that T4O is effective in treating chronic rosacea associated ocular demodex blepharitis.
... The presence of higher Demodex mite densities in rosacea compared with control skin has also been confirmed by other authors and using different techniques, including a 2012 PCR study that found density was 5.7 times and 2.9 times higher in subjects with rosacea with ETR/facial PPR or facial PPR than in healthy controls, respectively (22). The causal relationship between Demodex mites and rosacea is based not only on their higher density in patients with rosacea compared with healthy controls; other factors include histological damage and perifollicular infiltrate caused by the mite, possible activation of the toll-like receptor 2 (TLR-2) pathway leading to inflammatory skin changes, clinical improvement with pure acaricidal treatments and other arguments explained below (21,23). ...
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Rosacea, a chronic condition usually recognized by its visible presentation, can be accompanied by invisible symptoms, such as burning and stinging. This aim of this review is to gather the most recent evidence on burning and stinging, in order to further emphasize the need to address these symptoms. Inflammatory pathways can explain both the signs and symptoms of rosacea, but available treatments are still evaluated primarily on their ability to treat visible signs. Recent evidence also highlights the adverse impact of symptoms, particularly burning and stinging, on quality of life. Despite an increasing understanding of symptoms and their impact, the management of burning and stinging as part of rosacea treatment has not been widely investigated. Clinicians often underestimate the impact of these symptoms and do not routinely include them as part of management. Available therapies for rosacea have the potential to treat beyond signs, and improve burning and stinging symptoms in parallel. Further investigation is needed to better understand these benefits and to optimize the management of rosacea.
... Moreover, Demodex mites secrete proteolytic enzymes that destroy the intercellular junction, and their chelicera destroy the epithelial cells of the hair follicle, damaging the skin barrier (7). In addition, after they die, their ruptured bodies and fragments are released into the superficial dermis through damaged hair follicles that induce an immune response, forming granulomas (8). However, the exact underlying mechanism through which Demodex induces rosacea remains unclear. ...
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To develop an animal model of rosacea-like skin lesions caused by Demodex mites, a suspension of Demodex mites was injected into the skin of Japanese rabbits. The pathology of the skin lesion was assessed using H&E staining after 4 weeks of modeling. The skin lesions observed after 4 weeks were further treated with the recombinant bovine basic fibroblast growth factor (rbFGF) gel. Untreated lesions in the same rabbit were considered as the blank control. Erythema papules were observed in the model rabbit skin and could be observed most clearly in the 2nd week. Lumpy foreign bodies, telangiectasia and granuloma-like structure were observed in the model rabbit in the 1st, 2nd, and 3rd weeks, respectively. An organized granuloma-like structure was observed in the 4th week. The color of the skin lesions became lighter than that of the self-control after 4 weeks of rbFGF treatment. In conclusion, the model of Demodex-induced rosacea-like skin lesions can be developed through intradermal injection of suspension of Demodex mites into Japanese rabbits. The model can mimic the phenotype of skin lesions and histopathological manifestations in the Demodex mite-positive patient with rosacea.
... As a survival mechanism, Demodex mites may suppress the adaptive immune system by downregulating T-cell levels (Akilov and Mumcuoglu, 2004) or by blocking molecules required for an effective antiparasitic Th2 immune response (Liu et al., 2004). Low Demodex mite numbers may also downregulate the host immune TLR signalling pathway to facilitate their survival (Lacey et al., 2018). Moreover, analysis of skin-homing CD4 + T-cell subsets suggested that Demodex infestation induced an increase in the regulatory T-cell subpopulation compared to the Demodex-negative donors (Gazi et al., 2019). ...
Article
Demodex infestation and density changes remain one of the main challenges in some clinical settings. Tumour necrosis factor- α (TNF- α ) inhibitors have been recommended as a first-line treatment for ankylosing spondylitis (AS). However, there have been no studies investigating the impact of TNF- α inhibitor adalimumab on changes in the Demodex density in patients with AS. The aim of this study was to investigate Demodex density changes before and after adalimumab treatment and analyse the relationship between the Demodex density and clinical characteristics in AS. It was found that the Demodex density was positively correlated with age and C-reactive protein levels and the number of Demodex mites could increase after adalimumab treatment in AS.
... Although we cannot explain exactly whether the clinical improvement was caused by reducing Dds under a threshold level, even if not yet normalized, with a direct acaricidal effect or by anti-inflammatory properties of agents or both; the relatively high clinical improvement rate against the low normalization rate on Dds may suggest the anti-inflammatory effects of the agents are at the forefront. Since the mite has the ability for inducing inflammatory response, the effect of the agents in an anti-inflammatory way can be explained by suppression of mite-induced inflammation [19,[25][26][27]. ...
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Background: Demodicosis represents cutaneous diseases caused by cutaneous overpopulation of Demodex mites. The aim of this study was to evaluate the effect of different treatment options on Demodex densities (Dds) and clinical symptoms of patients with demodicosis. Methods: Patients with high Dds in two consecutive standardized skin surface biopsies (SSSB1>5 D/cm2 or SSSB2>10 D/cm²) and concomitant clinical symptoms were evaluated retrospectively. Measurements of treatment effectiveness included clinical improvement and normalization or reducing of Dds. Results: A total of 21 patients included in the study. Five patients received topical permethrin and crotamiton whereas 16 patients received systemic metronidazole in combination with topical permethrin and/or crotamiton. The treatment was continued with topical ivermectin in 2 patients who had failure with other treatments. The median treatment duration was 3 months (IQR 1-4). Pre- and post-treatment median Dds decreased 30 to 14 D/cm2 on SSSB1 whereas 81 to 80 D/cm2 on SSSB2, respectively. There was no statistically significant decrease in Dds on SSSB1 and SSSB2 after the treatment (p=0.173 and p=0.134, respectively). Clinical improvement was recorded in a total of 14 patients (66.6%) of whom only 2 patients (9.5%) had normalization on Dds. Additionally, topical ivermectin provided a rapid clinical improvement and normalization on Dds in both 2 patients. Conclusion: Irrespective of the treatment, more than two-thirds of the patients improved clinically without a significant change in Dds. This finding may suggest that the treatment response has been mostly associated with the anti-inflammatory properties of the agents. Topical ivermectin seems to be a more suitable treatment option for demodicosis with positive effects on both clinical findings and Dds.
... Demodex mites have been linked to various ophthalmological and dermatological disorders (4,(6)(7)(8). Although a causal explanation has yet to be established, several studies have demonstrated that Demodex density was substantially increased in rosacea, perioral dermatitis, and folliculitis patients compared to age-and sex-matched control groups (8)(9)(10)(11). Demodex mites were hypothesized to cause permanent microabrasions within the skin of rosacea patients. Accordingly, the deterioration of the skin barrier might contribute to cutaneous hypersensitivity. ...
... Deride saptanan Demodex yoğunluğu toll like reseptörlerin (TLR) aktive ya da inhibe olmalarını belirler. Normal deride az sayıda bulunan parazitin konak TLR sinyal yolağını baskıladığı buna karşılık artmış Demodex yoğunluğunun TLR2 yolağı üzerinden konak immün yanıtını artırarak deride enflamatuvar değişikliklere neden olabildiği öne sürülmektedir (4,26,27). ...
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Objective: The aim of the study was to investigate the Demodex prevalence in patients with dermatological complaints who were admitted to our hospital, and to evaluate the socio-demographic characteristics and risk factors of the patients. Methods: A total of 133 patients who were sent for Demodex screening were included and questionnaire for risk factors was administered. Samples were taken by standard superficial skin biopsy method and the different developmental stages were investigated under microscope. Results: Demodex species were found in 93 (69.9%) of the patients. Demodex folliculorum was found in 58 (62.4%) of the patients, Demodex brevis in 13 (14%), Demodex folliculorum and Demodex brevis in 4 (4.3%) and Demodex species in 18 (19.4%) of the patients. At least one of the Demodex species was found in 77.1% of patients with acne rosacea. No statistically significant relation was found between Demodex positivity and age, gender, number of weekly baths, use of makeup, and common towel use. Though statistically not significant, an increase of Demodex infestation with increasing age was observed. Conclusion: Demodex mite infestations are widespread worldwide without showing important racial and gender differences. In the present study, prevalence of Demodex infestation in patients with acne rosacea was high and this should be taken into consideration, when such patients are treated for their symptoms.
Article
Resumen Antecedentes y Objetivos: Existen antecedentes de asociación de la infestación por Demodex sp y acné vulgar. El objetivo fue evaluar si la infestación por Demodex sp. se asocia a acné vulgar grave en consulta externa de Hospital Regional Lambayeque. Material y Métodos: Estudio trasversal en 46 pacientes con acné grave y 92 pacientes con acné no grave. Se definió como acné vulgar grave a los participantes que tuvieron un grado ≥ 3 con la escala EGAE, la infestación por Demodex sp. se determinó realizando la Biopsia Cutánea Superficial, considerándose infestación si existieron más de 5 ácaros por cm2. Resultados: El 60,9% de los participantes fueron del sexo masculino con una mediana de edad de 18 años y un rango intercuartílico de 15 a 20 años, fueron provenientes del sector urbano (81,9%) y se encontró infestación por Demodex sp. en el 29,7%. En el análisis bivariado, se encontró asociación estadísticamente significativa entre acné vulgar grave e infestación por Demodex sp. (p=0,001), sexo (p=0,003), procedencia (p=0,015), antecedente paterno de acné (p=0,045), antecedente materno de acné (p=0,045) y tipo de piel (p<0,001). En el análisis multivariado la infestación por Demodex sp. estuvo 4,2 veces asociado a acné vulgar grave (IC: 1,6 – 10,9, p=0,003) ajustado por sexo, procedencia urbana, tratamiento previo, antecedentes paterno y materno de acné vulgar y la presencia de piel grasa. Conclusiones: La infestación por Demodex sp. se asocia al acné vulgar grave.
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Background Reflectance confocal microscopy (RCM), VISIA, and dermoscopy have emerged as promising tools for objective diagnosis and assessment of rosacea. However, little is known about the diagnostic value of these imaging systems for rosacea. Objectives To assess the diagnostic value of RCM, VISIA, and dermoscopy for rosacea by establishing a novel multilayer perceptron (MLP) model. Methods A total of 520 patients with rosacea and other facial diseases were included in this study. A total of 474 samples of dermoscopy data, 374 samples of RCM data, 434 samples of VISIA data, and 291 samples containing three data sources were collected. An MLP model was built with the total data to explore the association between the imageological features of each instrument and the probability of rosacea. Results Our MLP model revealed that the area under the receiver operating characteristic curve (AUROC) values of RCM, VISIA and dermoscopy for diagnosing rosacea were 0.5233, 0.5646 and 0.7971, respectively. The integration of these three tools with clinical data could further improve the accuracy of the predictive diagnosis to 0.8385. For the imageological features of each tool, abnormalities (hyperkeratosis or parakeratosis) in the stratum corneum were effective variables for excluding rosacea (odds ratio [OR], 0.4333) under RCM. The indicators of rosacea under VISIA included overall severity of erythema, erythema involving the cheek or superciliary arch, visible red blood vessels, and papules (OR = 2.2745, 3.1592, 1.8365, 2.8647, and 1.4260, respectively). The candidate variables of dermoscopy included yellow background, white background, uniform distribution of vessels, branched vessels, and reticular blood vessels (OR = 0.4259, 0.4949, 2.2858, 3.7444, and 2.4576, respectively). Conclusions RCM, dermoscopy, and VISIA each can present several imageological features and were of certain value for assisting rosacea diagnosis. The combined analysis of these three tools using our MLP model may be useful for improving the accuracy of diagnosing rosacea.
Article
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.
Article
Background and objectives: Infestation with Demodex mites has been associated with acne vulgaris. The aim of this study was to explore the association between Demodex infestation and severe acne vulgaris in outpatients seen at Hospital Regional Lambayeque in Chiclayo, Peru. Material and methods: We conducted a cross-sectional study of 46 patients with severe acne and 92 patients with nonsevere acne. Severe acne vulgaris was diagnosed if the score was 3 or more on the Spanish Acne Severity Scale (EGAE, in its Spanish acronym). Demodex infestation was diagnosed when a skin surface biopsy showed more than 5 mites/cm². Results: The patients had a median age of 18 years (interquartile range, 15-20 years), 60.9% were male, 81.9% lived in an urban area, and 29.7% were infested with Demodex mites. In the bivariate analysis, severe acne vulgaris was significantly associated with Demodex infestation (P = .001), sex (P = .003), residence (P = .015), a paternal history of acne (P = .045), a maternal history of acne (P = .045), and type of skin (P < .001) In the multivariate analysis, after adjustment for male sex, urban residence, previous treatment, maternal and paternal history of acne vulgaris, and an oily skin type, patients with Demodex infestation were 4.2 times more likely to have severe acne vulgaris (95% CI, 1.6-10.9; P = .003). Conclusion: Demodex infestation was associated with severe acne vulgaris in outpatients at our hospital.
Article
Background and objectives: Ocular rosacea is a special manifestation of rosacea with unknown etiology. Eye involvement in rosacea patients is surprisingly common; however, it is often underdiagnosed, resulting in inappropriate treatment. We aimed to provide an updated epidemiologic perspective on ocular rosacea in Germany to improve patient care. Patients and methods: Data of 777 rosacea patients were assessed using a detailed online questionnaire regarding ocular and skin symptoms, previous dermatological and ophthalmological consults, presence of type 1 hypersensitivities, and Demodex testing. All data were statistically analyzed. Results: Most patients reported ocular symptoms (399/777, 51.4%), including red eyes (179/399, 44.9%), itching (187/399, 46.9%), sty or chalazion (309/399, 77.4%), and dryness (108/399, 27.1%). Ocular rosacea was confirmed in 149/309 cases who consulted an ophthalmologist (45.3%). A total of 159/399 (39.8%) had no pre-existing allergies. Eye involvement was significantly associated with the presence of skin symptoms (P < 0.05), impacting patients' general well-being and overall treatment satisfaction. About half of Demodex-positive patients (21/45, 46.7%) showed ocular symptoms. Conclusions: Eye involvement in rosacea patients was common, often presenting with unspecific symptoms.
Article
D. folliculorum, and D. brevis are human ectoparasites living in hair follicles and sebaceous glands of the skin, respectively, and most commonly on the face. They are normal flora, but D. folliculorum can cause disease when it proliferates excessively or penetrates the dermis. Increased densities of Demodex have been reported in rosacea‐by reflectance confocal microscopy (RCM), two consecutive SSSB (2‐SSSB)7 and a superficial needle‐scraping method.
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Purpose of Review Ongoing investigations of the human skin microbiome strongly suggest a connection to skin diseases and skin health. This review provides an overview of recent literature on the skin microbiome in relation to skin diseases, with a specific focus on common inflammatory skin conditions, such as atopic dermatitis, psoriasis, hidradenitis suppurativa, acne, and rosacea. Recent Findings In healthy subjects, the skin microbiome mediates fundamental processes involving the immune response and epidermal development and differentiation. Microbiome characteristics in inflammatory skin diseases differ depending on disease, as both topography and disease severity and even host genetics seem to influence the microbiome composition. Not only the bacterial species are important but also different strains within the same species can act differently, where some can be commensal and protect against microbial dysbiosis, whereas others can induce skin inflammation and immune reactions in humans. Summary The interplay between skin microbes, host genetics, and the immune system is anticipated to be of importance for both the development and severity of many skin diseases. However, the causality of specific pathogens and the effect on the pathogenesis in relation to inflammatory skin diseases is yet to be understood.
Article
Linked Article: Webster et al. Br J Dermatol 2020; 183:471–479.
Chapter
Ayres et al. are generally credited as being amongst the first authors to suggest that Demodex mites might play a role in the pathology of rosacea. This was because it has been long recognized that these mites are more abundant in the facial skin of patients with papulopustular rosacea (PPR) than in the skin of normal subjects. Furthermore, mites or portions of mites are not uncommonly found in the histopathology sections of biopsies taken from the facial skin of patients with PPR rosacea, usually with intense surrounding inflammatory infiltrate. The recent advance in topical ivermectin (a known anti-mite therapy) as an effective treatment of rosacea has supported the concept of these mites being of pathogenic importance in this common skin disorder. In this book chapter, we will describe the biology of Demodex, the technical challenge of their study, and the possible mechanisms by which Demodex may contribute to the pathophysiology of rosacea.
Article
Rosacea is a common chronic skin disease affecting mostly people aged 40 and above, with currently no cure. When it affects the eyelids and periocular skin, it leads to dry eye and potentially corneal damage. Research performed over the last decade shed light into the potential mechanisms leading to skin hypersensitivity and provided promising avenues for development of novel, rational therapeutics aimed at reducing the skin inflammatory state. In this review, we discuss the current knowledge on the mechanisms of rosacea in general and of periocular skin-affecting disease in particular, identify key questions that remain to be answered in future research, and offer a disease model that can explain the key characteristics of this disease, with particular emphasis on a potential positive feedback loop that could explain both the acute and chronic features of rosacea.
Article
The skin microbiome plays a critical role in skin homeostasis and disorders. UV-radiation is the major cause for nonmelanoma skin cancer, but other risk factors including immune suppression, chronic inflammation, and antibiotic usage, suggest the microbiome as an additional, unexplored risk factor and potential disease biomarker. The overarching goal was to study the skin microbiome in squamous cell carcinoma (SCC) and pre-malignant actinic keratosis (AK) compared to healthy skin to identify skin cancer-associated changes in the skin microbiome. We performed a high-resolution analysis of shotgun metagenomes of AK and SCC to healthy skin, revealing microbial community shifts specific to AK and SCC. Most prominently, the relative abundance of pathobiont Staphylococcus aureus was increased at the expense of commensal Cutibacterium acnes in SCC compared to healthy skin, and enrichment of functional pathways in SCC reflected this shift. Notably, C. acnes associated with lesional vs. healthy skin differed at the strain level, suggesting specific functional changes associated with its depletion in SCC. Our study revealed a transitional microbial dysbiosis from healthy skin to AK to SCC, supporting further investigation of the skin microbiome for use as a biomarker and providing hypotheses for studies investigating how these microbes might influence skin cancer progression.
Article
Demodex mites are microscopic arachnids found in the normal skin of many mammals. In humans, it is well established that Demodex mite density is higher in patients with the skin condition rosacea, and treatment with acaricidal agents is effective in resolving symptoms. However, pathophysiology of rosacea is complex and multifactorial. In dogs, demodicosis is a significant veterinary issue, particularly the generalised form of the disease which can be fatal if untreated. In each species, clinical and molecular studies have shown that the host's immunological interactions with Demodex mites are an important, but not fully understood, aspect of how Demodex can live in the skin either as a harmless commensal organism or as a pathogenic agent. This review outlines the role of Demodex mites in humans and dogs, considering morphology, prevalence, symptoms, diagnosis, histology treatment, and pathogenesis.
Article
Signal transducer and activator of transcription (STAT)1 heterozygous gain‐of‐function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In‐depth immune phenotyping and functional studies were used to characterize the patients. We identified 5 patients (3 males) from 2 non‐consanguineous Jewish families. Mean age at presentation was 11.11 (range: 0.58–24) years. Clinical presentation included CMCC, chronic demodicosis, and immune dysregulation in all patients. Whole‐exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in 4 of the 5 patients. Immunophenotyping demonstrated increased phosphorylated STAT1 in response to interferon‐α stimuli in all patients. The patients also exhibited decreased T‐cell proliferation capacity and low counts of interleukin‐17‐producing T cells, as well as low FOXP3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, management of patients with chronic demodicosis should include an immunogenetic evaluation.
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The expansion of knowledge about the microbiome, which is a broad term that entails the collective genetic content of microbiota as a community of microorganisms living on or in a host, has challenged our notion about how microbes can influence human health and disease. This article presents the Human Microbiome Project as the first big research endeavor that confirmed how the microbiome can substantially differ even among healthy individuals and continues with a discussion of the structure and dynamics of healthy microbiota and its link with metabolism. After a review of the state-of-the-art methods for studying the human microbiome in the laboratory, the second half of this article is focused on the imbalances in microbial communities (also known as dysbiosis) and its purported connections with various diseased states, particularly for the intestinal, oral, urogenital and skin microbiomes. The ultimate objective of human microbiome research is to optimize health and disease management, which will be facilitated by the improved analysis of functional host-microbiome interactions.
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Ocular rosacea is a chronic potentially sight-threatening inflammatory condition, which can occur in approximately 20% of patients without skin involvement. However, an accurate diagnosis of ocular rosacea has not been defined yet due to its rather nonspecific symptoms and clinical findings. Therefore, this article updates the current recommendations for diagnosis and treatment of ocular rosacea and the previously published consensus recommendations from the ROSCO expert panel on the management of rosacea.
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Human hair follicles (HF) carry complex microbial communities that differ from skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in that it provides a moist, less acidic, and relatively UV‐protected environment, part of which is immune‐privileged, thus facilitating microbial survival. Here we review the current understanding of the human HF microbiome and its potential physiological and pathological functions, including in folliculitis, acne vulgaris, hidradenitis suppurativa, alopecia areata and cicatricial alopecias. While reviewing the main human HF bacteria, such as Propionibacteria, Corynebacteria, Staphylococci and Streptococci, viruses, fungi and parasites as human HF microbiome constituents, we advocate a broad view of the HF as an integral part of the human holobiont. Specifically, we explore how the human HF may manage its microbiome via the regulated production of antimicrobial peptides (such as cathelicidin, psoriasin, RNAse7 and dermcidin) by HF keratinocytes, how the microbiome may impact on cytokine and chemokine release from the HF, examine hair growth‐modulatory effects of antibiotics, and ask whether the microbiome affects hair growth in turn. We highlight major open questions and potential novel approaches to the management of hair diseases by targeting the HF microbiome.
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Over the past 15 years, numerous clinical, epidemiological and physiopathological articles have been published on rosacea. There is now increasing evidence that rosacea is an inflammatory disease characterised by abnormal innate immune response, major vascular changes, and increased colonisation by Demodex mites, along with a genetic predisposition and multiple external aggravating factors. It is thus possible to define treatment targets and possible treatments: 1) permanent vascular changes (medical and instrumental treatments); 2) flushing (betablockers, botulinum toxin); 3) innate immunity (antibiotics, nonspecific antioxidants and anti-inflammatory molecules); 4) a neurovascular component (analgesics, antidepressants); 5) Demodex (antiparasitic drugs); 6) microbiome; 7) skin barrier impairment (cosmetics and certain systemic drugs); 8) sebaceous glands (isotretinoin, surgery); 9) environmental factors (alcohol, coffee, UV exposure). Treatment recommendations are now available in many countries and benefit from the new phenotypic approach to rosacea, in which every sign or symptom is considered separately rather than having to deal with overlapping subtypes. Since the 2000s, many good quality clinical trials have been published in the field of rosacea and many others are still ongoing. Rosacea is a complex disease involving many different mechanisms and with numerous possible treatments, but there are still some important unmet needs with regard to optimal care.
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The human skin microbiota is essential for maintaining homeostasis and ensuring barrier functions. Over the years, the characterization of its composition and taxonomic diversity has reached outstanding goals, with more than 10 million bacterial genes collected and cataloged. Nevertheless, the study of the skin microbiota presents specific challenges that need to be addressed in study design. Benchmarking procedures and reproducible and robust analysis workflows for increasing comparability among studies are required. For various reasons and because of specific technical problems, these issues have been investigated in gut microbiota studies, but they have been largely overlooked for skin microbiota. After a short description of the skin microbiota, the review tackles methodological aspects and their pitfalls, covering NGS approaches and high throughput culture-based techniques. Recent insights into the “core” and “transient” types of skin microbiota and how the manipulation of these communities can prevent or combat skin diseases are also covered. Finally, this review includes an overview of the main dermatological diseases, the changes in the microbiota composition associated with them, and the recommended skin sampling procedures. The last section focuses on topical and oral probiotics to improve and maintain skin health, considering their possible applications for skin diseases.
Article
Background Rosacea is a chronic inflammatory skin disease whose psychological consequences severely affect patient’s quality of life. Objective To identify candidate genes of rosacea for potential development of new target therapies. Methods Gene Expression Omnibus datasets were retrieved to obtain differentially expressed genes (DEGs) between rosacea patients and healthy controls. Gene ontology (GO) analyses were used to identify functions of candidate genes. Related signaling pathways of DEGs were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis. Protein-protein interaction (PPI) networks were applied using search tools for the retrieval of interacting genes/proteins and modulations involving PPI networks were evaluated with use of the MCODE app. Results Samples from 19 rosacea patients and 10 healthy controls of dataset GSE65914 were enrolled. A total of 215 DEGs, 115 GO terms and 6 KEGG pathways were identified. A total of 182 nodes and 456 edges were enriched in PPI networks. Maximal clusters showed 15 central nodes and 96 edges. The toll-like receptor (TLR) signaling pathway was the most significant pathway detected and 5 DEGs were identified as candidate genes which included TLR2, C-C motif chemokine (CCL) 5, C-X-C motif chemokine ligand (CXCL) 9, CXCL10 and CXCL11. The results were verified in rosacea patients with use of real-time polymerase chain reaction and immunohistochemistry. Cell-type enrichment analysis revealed 8 lymphocytes that were enriched in rosacea patients. Conclusions The results suggest that both innate and adaptive immune responses were involved in the etiology of rosacea. Five DEGs in the TLR signaling pathway may serve as potential therapeutic target genes.
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Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a "developmental march" of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating "human disease model" for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology.
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Chitin, after cellulose the second most abundant polysaccharide in nature, is an essential component of exoskeletons of crabs, shrimps and insects and protects these organisms from harsh conditions in their environment. Unexpectedly, chitin has been found to activate innate immune cells and to elicit murine airway inflammation. The skin represents the outer barrier of the human host defense and is in frequent contact with chitin-bearing organisms, such as house-dust mites or flies. The effects of chitin on keratinocytes, however, are poorly understood. We hypothesized that chitin stimulates keratinocytes and thereby modulates the innate immune response of the skin. Here we show that chitin is bioactive on primary and immortalized keratinocytes by triggering production of pro-inflammatory cytokines and chemokines. Chitin stimulation further induced the expression of the Toll-like receptor (TLR) TLR4 on keratinocytes at mRNA and protein level. Chitin-induced effects were mainly abrogated when TLR2 was blocked, suggesting that TLR2 senses chitin on keratinocytes. We speculate that chitin-bearing organisms modulate the innate immune response towards pathogens by upregulating secretion of cytokines and chemokines and expression of MyD88-associated TLRs, two major components of innate immunity. The clinical relevance of this mechanism remains to be defined.
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The nuclear factor-κB (NF-κB) family of transcription factors plays a central part in the host response to infection by microbial pathogens, by orchestrating the innate and acquired host immune responses. The NF-κB proteins are activated by diverse signalling pathways that originate from many different cellular receptors and sensors. Many successful pathogens have acquired sophisticated mechanisms to regulate the NF-κB signalling pathways by deploying subversive proteins or hijacking the host signalling molecules. Here, we describe the mechanisms by which viruses and bacteria micromanage the host NF-κB signalling circuitry to favour the continued survival of the pathogen.
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A diverse environment challenges skin to maintain temperature, hydration, and electrolyte balance while also maintaining normal immunological function. Rosacea is a common skin disease that manifests unique inflammatory responses to normal environmental stimuli. We hypothesized that abnormal function of innate immune pattern recognition could explain the enhanced sensitivity of patients with rosacea, and observed that the epidermis of patients with rosacea expressed higher amounts of Toll-like receptor 2 (TLR2) than normal patients. Increased expression of TLR2 was not seen in other inflammatory skin disorders such as atopic dermatitis or psoriasis. Overexpression of TLR2 on keratinocytes, treatment with TLR2 ligands, and analysis of TLR2-deficient mice resulted in a calcium-dependent release of kallikrein 5 from keratinocytes, a critical protease involved in the pathogenesis of rosacea. These observations show that abnormal TLR2 function may explain enhanced inflammatory responses to environmental stimuli and can act as a critical element in the pathogenesis of rosacea.
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Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics.
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To better understand the link between parasite infections and the course of multiple sclerosis (MS), we studied the role of TLRs in helminth product recognition by dendritic cells (DCs) and B cells. Baseline expression of TLR2 was significantly higher in infected-MS patients compared with uninfected MS subjects or healthy controls. Moreover, cells exposed to TLR2 agonists or to soluble egg Ag (SEA) from Schistosoma mansoni resulted in significant TLR2 up-regulation. SEA suppressed the LPS-induced DCs production of IL-1beta, IL-6, IL-12, and TNF-alpha and enhanced TGF-beta as well as IL-10 production. Similarly, after exposure to SEA, anti-CD40-activated B cells increased IL-10 production. Both processes were MyD88 dependent. In addition, SEA down-regulated the expression of LPS-induced costimulatory molecules on DCs in a MyD88-independent manner. DCs stimulation by SEA and TLR2 agonists induced increasing phosphorylation of the MAPK ERK1/2. Neither stimulus showed an effect on p38 and JNK1/2 phosphorylation, however. Addition of the ERK1/2 inhibitor U0126 was associated with dose-dependent inhibition of IL-10 and reciprocal enhancement of IL-12. Finally, cytokine effects and changes observed in DCs costimulatory molecule expression after SEA exposure were lost when TLR2 expression was silenced. Overall, these findings indicate that helminth molecules exert potent regulatory effects on both DCs and B cells through TLR2 regulation conducted via different signaling pathways. This knowledge could prove critical in developing novel therapeutic approaches for the treatment of autoimmune diseases such as MS.
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Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred. To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea. A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study). Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers. One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel. Subjects were evaluated monthly for up to 6 months to determine relapse rates. Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed. In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P<.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P<.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%). In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.
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In previous studies, we demonstrated that allergenic house dust mite proteases are potent inducers of proinflammatory cytokines from the respiratory epithelium, although the precise mechanisms involved were unclear. In this study, we investigated whether this was achieved through activation of protease-activated receptor (PAR)-1 or -2. Pretreatment of A549 respiratory epithelial cells with the clinically important cysteine protease allergen, Der p 1, ablated subsequent PAR-1, but not PAR-2 agonist peptide-induced IL-6 and IL-8 release. HeLa cells transfected with the plasmid coding for PAR-2, in contrast to PAR-1, released significant concentration of IL-6 after exposure to Der p 1. Exposure of HeLa cells transfected with either PAR-1/enhanced yellow fusion protein or PAR-2/enhanced yellow fusion protein to Der p 1 caused receptor internalization in the latter cells only, as judged by confocal microscopy with re-expression of the receptor within 120-min postenzyme exposure. Der p 1-induced cytokine release from both A549 and transfected HeLa cells was accompanied by changes in intracellular Ca(2+) concentrations. Desensitization studies showed that Der p 1 pretreatment of the A549 cells resulted in the abolition of both trypsin- and PAR-2 agonist peptide-induced Ca(2+) release, but not that induced by subsequent exposure to either thrombin or PAR-1 agonist peptide. These data indicate for the first time that the house dust mite allergen Der p 1-induced cytokine release from respiratory epithelial cells is, in part, mediated by activation of PAR-2, but not PAR-1.
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Demodex folliculorum and Demodex brevis are obligatory parasites in the hair follicles and in the pilosebaceous glands. Although most people are infested with these mites, only a small number develop the clinical symptoms of demodicosis. The objective of this study was to determine the distinguishing features of the immune response to the infestation of the skin by Demodex mites. Twenty-nine patients with human demodicosis and 13 age- and sex-matched healthy subjects participated in the study. The presence of mites was determined by microscopic inspection of secretion from sebum glands. The immune response was evaluated in the peripheral blood by identifying membrane markers of different immune cells using monoclonal antibodies, while the concentration of immunoglobulin (Ig)A, IgM and IgG was calculated by simple radial immunodiffusion using anti-IgA, anti-IgM and anti-IgG. The level of circulating immune complexes and total haemolytic complement, as well as the preparatory and digestive function of neutrophils, and the functional activity of leucocytes were also studied. The absolute number of CD95+ was higher in patients with demodicosis. The absolute number of CD3+, CD4+, CD8+ and CD16+ cells, the ratio CD3+/CD20+ and the functional activity of leucocytes were significantly lower in individuals infested with Demodex mites. No significant differences were found in the percentage and absolute number of CD20+ cells, the ratio of CD4+/CD8+ T-cell subpopulations, circulating immune complexes, level of serum complement activity (CH(50)), activity and index of phagocytosis and the levels of IgA, IgM and IgG antibodies between individuals infested with Demodex mites and the control group. The readiness of lymphocytes to undergo apoptosis increases in parallel to the increasing density of the mites. This could be the result of local immunosuppression caused by the mites, which allows them to survive in the host skin.
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Demodicoses are thought to be rare, occurring mainly for patients with immunosuppression. We sought to demonstrate the high frequency of demodicoses and the overlapping with papulopustular rosacea (PPR) . We conducted a prospective epidemiologic study among 10 dermatologists. High Demodex density (Dd) was confirmed by standardized skin surface biopsy. In all, 4372 diagnoses, in which 115 were demodicoses, were collected among 3213 patients. Demodicosis was the 9th most frequent diagnosis (13th new). Each dermatologist observed an average of 2.4 demodicoses a week (1.2 new). The proportion of demodicoses varied greatly according to the dermatologist. The general status was good in 110 patients; only 3 had known immunodeficiency. The most frequent symptoms were follicular scales (71%) and telangiectasia (63%). The mean Dd was higher in pityriasis folliculorum (m = 61 D/cm 2 ) than in PPR (m = 36 D/cm 2 ; P = .04); 42 patients with PPR had a high Dd, 6 had a low Dd. Demodicoses are frequent and occur among patients who are immunocompetent. PPR with normal Dd are rare.
Article
Diagnosing papulopustular rosacea is not always straightforward; no specific diagnostic test is currently available. A high density of Demodex mites is consistently observed in this condition. This retrospective study assesses an improved method for evaluating Demodex density among 1,044 patients presenting to our dermatology practice. The skin was cleaned with ether and Demodex densities were measured in 2 consecutive standardized skin surface biopsies taken from the same site. Mean densities in patients with rosacea and demodicosis were much higher than those in healthy controls and patients with other facial dermatoses. The optimal cut-off values for the 2 biopsies were combined and the resultant criterion (presence of a first biopsy density > 5 Demodex/cm2 or a second biopsy density> 10 Demodex/cm2) enabled confirmation of a diagnosis of rosacea or demodicosis with a sensitivity of 98.7% and specificity of 95.5%, making this a valuable diagnostic tool for dermatologists in routine clinical practice.
Article
Background: Patients with rosacea have increased amounts of cathelicidin and protease activity but their usefulness as disease biomarkers is unclear. Objective: We sought to evaluate the effect of doxycycline treatment on cathelicidin expression, protease activity, and clinical response in rosacea. Methods: In all, 170 adults with papulopustular rosacea were treated for 12 weeks with doxycycline 40-mg modified-release capsules or placebo in a multicenter, randomized, double-blind, placebo-controlled study. Clinical response was compared with cathelicidin and protease activity in stratum corneum samples obtained by tape strip and in skin biopsy specimens obtained from a random subset of patients. Results: Treatment with doxycycline significantly reduced inflammatory lesions and improved investigator global assessment scores compared with placebo. Cathelicidin expression and protein levels decreased over the course of 12 weeks in patients treated with doxycycline. Low levels of protease activity and cathelicidin expression at 12 weeks correlated with treatment success. Low protease activity at baseline was a predictor of clinical response in the doxycycline treatment group. Limitations: Healthy control subjects were not studied. Conclusions: Improved clinical outcome correlated with reduced cathelicidin and protease activity, supporting both the mechanism of doxycycline and the potential of these molecules as biomarkers for rosacea.
Article
Demodex mites are the largest and most complex organisms of the skin microflora. How they interact with the innate and adaptive immune systems is unknown. Their potential to have a pathogenic role in the causation of human skin disorders causes continued speculation. With growing interest in the microflora of human skin and its relevance to cutaneous health, the role of Demodex mites needs to be better understood. The main challenges facing scientists investigating the role of these organisms and possible solutions are reviewed under the following headings: (1) Determining the mite population in skin, (2) Transporting, extracting and imaging live mites, (3) Maintaining mites viable ex vivo and (4) Establishing methods to determine the immune response to Demodex mites and their internal contents.
Article
Detection of and response to microbial infections by the immune system depends largely on a family of pattern-recognition receptors called Toll-like receptors (TLRs). These receptors recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. Recognition of ligands by TLRs leads to a series of signaling events resulting in induction of acute responses necessary to kill the pathogen. TLRs are also responsible for the induction of dendritic cell maturation, which is responsible and necessary for initiation of adaptive immune responses. Although TLRs control induction of adaptive immunity, it is not clear at this point how responses are appropriately tailored by individual TLRs to the advantage of the host.
Article
Rosacea is a common chronic inflammatory dermatosis of unclear origin. It has been associated with systemic comorbidities, but methodical studies addressing this association are lacking. We evaluated: (1) the association between rosacea and systemic comorbidities; and (2) if the severity of rosacea is impacted by comorbidities. This was a case-control study: patients with rosacea were matched (1:1) to rosacea-free control subjects by age, sex, and race. Relative risk estimates were calculated using logistic regression as odds ratios with 95% confidence intervals. Among 130 participants (65 patients/65 control subjects), we observed a significant association between rosacea and allergies (airborne, food), respiratory diseases, gastroesophageal reflux disease, other gastrointestinal diseases, hypertension, metabolic and urogenital diseases, and female hormone imbalance. Compared with mild rosacea, moderate to severe rosacea was significantly associated with hyperlipidemia, hypertension, metabolic diseases, cardiovascular diseases, and gastroesophageal reflux disease. This was a case-control study with moderate sample size. Associated medical conditions were self-reported and could not always be confirmed by medication use and medical records. Rosacea is associated with numerous systemic comorbid diseases in a skin severity-dependent manner. Physicians should be aware of these associations to provide comprehensive care to patients with rosacea, especially to those with more severe disease. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Article
Rosacea is a chronic inflammatory skin disease. Inflammation plays a prominent role in atherosclerosis and its complications. We sought to investigate the associations of rosacea with cardiovascular disease risk factors and cardiovascular diseases from a nationwide population-based database. A total of 33,553 patients with rosacea and 67,106 age- and gender-matched control subjects were identified from the National Health Insurance Research Database in Taiwan from 1997 to 2010. Multivariate logistic regressions were performed to compare the odds of comorbidities between the 2 groups. Dyslipidemia (odds ratio 1.41; 95% confidence interval 1.36-1.46), coronary artery disease (odds ratio 1.35, 95% confidence interval 1.29-1.41), and hypertension (odds ratio 1.17, 95% confidence interval 1.12-1.21) were significantly associated with rosacea. Coronary artery disease remained independently associated with rosacea after adjustment for hypertension, diabetes mellitus, and dyslipidemia. Male patients with rosacea had higher risks for all comorbidities than female patients with rosacea. The National Health Insurance Research Database does not contain information regarding rosacea subtypes or disease severity, or laboratory data. Patients with rosacea are more likely to have dyslipidemia and hypertension. They are also at increased risk of coronary artery disease after adjustment for cardiovascular disease risk factors. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Article
Background: Rosacea is a common problem that is underdiagnosed; if left untreated can result in physical disfigurement and emotional distress. Objective: We reviewed the current literature to determine the degree of psychosocial impact of rosacea and the importance of treatment. We also reviewed the current treatment options. Methods: A search of the MEDLINE, EMBASE, and psycINFO databases from 1946 to present was performed to identify previous articles regarding the psychosocial and quality-of-life (QoL) impact of rosacea. Results: A total of 17 studies were found that focused on the following areas: impact of disease on QoL, improvement of QoL with treatment, and willingness to pay. Limitations: Reviewed articles used different measurement systems to quantify impact on QoL making comparisons between studies difficult to interpret. Conclusion: Patients with rosacea have higher incidences of embarrassment, social anxiety, depression, and decreased QoL compared with the rest of the population. Adequate treatment of symptoms results in improvement of QoL in patients with rosacea. New options that target the facial erythema of rosacea may help mitigate the negative psychological impact of rosacea.
Article
Treatments for papulopustular rosacea (PPR) are limited. To demonstrate the efficacy and safety of once-daily ivermectin 1% cream in subjects with moderate to severe PPR. Two identically designed, randomized, double-blind, controlled studies of ivermectin 1% cream (IVM 1%) or vehicle once daily for 12 weeks were conducted in subjects with moderate to severe PPR. Efficacy assessments were Investigator's Global Assessment (IGA) of disease severity and inflammatory lesion counts. Safety assessments included incidence of adverse events (AEs) and local tolerance parameters. Subjects evaluated their rosacea and completed satisfaction and quality of life (QoL) questionnaires. In both studies, a greater proportion of subjects in the IVM 1% group achieved treatment success (IGA "clear" or "almost clear"): 38.4% and 40.1% vs 11.6% and 18.8% for vehicle (both P<.001), respectively. Ivermectin was superior to vehicle in terms of reduction from baseline in inflammatory lesion counts (76.0% and 75.0% vs 50.0% for both vehicle groups, respectively). For all endpoints, starting at week 4 and continuing through week 12, IVM 1% was statistically significantly superior (P<.001). Fewer subjects treated by IVM 1% reported dermatologic AEs, and a higher proportion of subjects were observed to have no skin dryness or itching compared to vehicle. Significantly more subjects receiving IVM 1% reported having an "excellent" or "good" improvement, along with an improved QoL. Ivermectin 1% cream was effective and safe in treating inflammatory lesions of papulopustular rosacea. J Drugs Dermatol. 2014;13(3):316-323.
Article
Case definitions are critical in epidemiologic research. However, modern disease indicators must now consider complex data from gene-based research along with traditional clinical parameters. Rosacea is a skin disorder with multiple signs and symptoms. In individuals, these features may be multiple or one may predominate. While studies on the epidemiology of rosacea have previously been sparse, there has been a recent increase in research activity. A broader body of epidemiological information that includes a greater variety of countries beyond Northern Europe and general population-based demographics is needed. As there are operational issues in current case definitions of rosacea subtypes-rationalization and standardization-universal consistent applications in future research is also imperative. Further improvement in disease definition combining new research information along with clinical pragmatism should increase the accuracy of rosacea case ascertainment and facilitate further epidemiological research.
Article
To explore the association between Demodex infestation and rosacea and the pathogenesis of demodicosis rosacea by means of a meta-analysis. Electronic searches of the ISI Web of Knowledge (Science Citation Index, ISTP [Index to Scientific & Technical Proceedings], Journal Citation Reports, BP [BIOSIS Preview], INSPEC [Ination Service in Physics, Electronics Technology, and Computer and Control], and DII [Derwent Innovation Index]), MEDLINE, and CNKI (China National Knowledge Infrastructure) databases (January 1, 1950, to December 31, 2009). We also performed hand searches of reference lists and conference proceedings. Predefined selection criteria were applied to all published case-control studies that analyzed the association between Demodex infestation and rosacea. Two of us independently extracted data from the included studies. For disputed articles, a third party mediated whether to include the study. Forty-eight English- and Chinese-language articles, which covered 10 different countries and 28 527 participants, were eligible. The pooled odds ratio in random-effects models is 7.57 (95% confidence interval, 5.39-10.62). Stability is good according to sensitivity analysis. The fail-safe number is 18 456 in the quantitative analysis of publication bias. A significant association exists between Demodex infestation and the development of rosacea. Demodex infestation is a vital risk factor for rosacea according to the time-to-event relationship, and the degree of infestation played a more important role than did the mite infestation rate in the development of rosacea.
Article
1. Histological data are given about the location and frequency of the different stages of the life history of D. folliculorum in the pilo-sebaceous apparatus of man. These data are examined statistically and the relative durations of each stage and their movements in the follicle are deduced from them. 2. A method of in vitro culture is described and data are given about the longevity of the various stages of the life history. 3. Experiments on the behaviour of the different motile stages of the mite are described. It is concluded that the deutonymph is the distributive stage, and that distribution occurs over the skin surface. 4. The life history is reconstructed by a synthesis of the evidence presented. The life-cycle lasts approximately 14½ days, the life span of each stage of it being: ovum 60 hr., larva 36 hr., protonymph 72 hr., deutonymph 60 hr., adult 120 hr. Interval between copulation and oviposition 12 hr. This work was largely carried out in the Department of Pathology of the Institute of Dermatology, London, and I wish to thank the Director of Pathology, Dr J. O. Oliver, for making available to me the facilities of his department, and for his advice and interest during the progress of the work. The photographs were prepared by Mr R. H. Lunnan of the Photographic Department of the Institute of Dermatology. I am indebted to the Dean of the Institute of Dermatology for permission to publish the photographs. I am grateful to Mr T. E. Hughes of the Department of Zoology, Birkbeck College, University of London, for his advice at all times, and to Miss Hilda Davies of the Department of Statistics, University of Sheffield, for help with statistical methods and to Mr W. Moseley, who prepared the text figures. Finally, I wish to express my thanks to Professor I. Chester Jones and Dr E. T. B. Francis of the Department of Zoology, University of Sheffield, for reading the manuscript and for their help in its preparation.
Article
Forty patients with rosacea were entered into a study comparing clarithromycin with doxycycline in the systemic treatment of mild and severe rosacea. The patients, 25 women and 15 men, aged from 26 to 62 years, were subdivided into two homogeneous groups with regard to age, sex, and disease seventy. The first group of 23 patients, 14 women and 9 men, was treated with 250 mg of clarithromycin for 4 weeks twice daily, and then with 250 mg once daily for the following 4 weeks. The second group of 17 patients, 11 women and 6 men was treated with 100 mg of doxycycline for 4 weeks twice daily, and then with 100 mg once a day for the following 4 weeks. Both objective and subjective evaluations of the dermatosis were performed prior to therapy and after 4, 6, and 8 weeks of treatment.
Article
Rosacea is a chronic facial skin disease of unclear origin. Epidemiological data are scarce and controversial, with reported prevalences ranging from 0·09% to 22%. To our knowledge, incidence rates have not been quantified before. In this observational study we quantified incidence rates of diagnosed rosacea in the U.K. and described demographic characteristics and the prevalence of ocular symptoms in patients with rosacea. We compared lifestyle factors such as smoking and alcohol consumption between patients with rosacea and controls. Using the U.K.-based General Practice Research Database, we identified patients with an incident diagnosis of rosacea between 1995 and 2009 and matched them (1:1) to rosacea-free control patients. We assessed person-time of all patients at risk and assessed incidence rates of rosacea, stratified by age, sex, year of diagnosis and region. We identified 60,042 rosacea cases and 60,042 controls (61·5% women). The overall incidence rate for diagnosed rosacea in the U.K. was 1·65 per 1000 person-years. Rosacea was diagnosed in some 80% of cases after the age of 30 years. Ocular symptoms were recorded in 20·8% of cases at the index date. We observed a significantly reduced relative risk of developing rosacea among current smokers (odds ratio 0·64, 95% confidence interval 0·62-0·67). Alcohol consumption was associated with a marginal risk increase. We quantified incidence rates and characteristics of patients with rosacea diagnosed in clinical practice in a large epidemiological study using primary care data from the U.K. Smoking was associated with a substantially reduced risk of developing rosacea.
Article
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.
Article
The prevalence and pathogenesis of rosacea is uncertain. Previously, studies used varying definitions of disease and have not explored the relationship of its prevalence to ultraviolet (UV) exposure or photodamage. We investigated the prevalence of papulopustular rosacea (PPR) and its relationship to UV radiation exposure in 1000 randomly selected Irish individuals. A total of 1000 individuals (500 with low UV exposure and 500 with high UV exposure) were examined. PPR was diagnosed using a standardized definition and photodamage was assessed using a photodamage scale. The prevalence of PPR was 2.7%. PPR prevalence was not significantly related to photodamage or UV exposure. The power to compare UV exposure among those with and without PPR was limited. PPR prevalence in Ireland was 2.7%. UV radiation exposure does not appear to affect the prevalence of PPR.
Article
Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of cytokines and other inflammatory mediators. Immunopharmacological studies can provide new information on the immunomodulatory activities of some drugs, including their effect on cytokine productions. For this reason, we first investigated the efficacy of avermectin on cytokine levels induced by LPS in vitro, and we found that avermectin can significantly regulate tumor necrosis factor alpha, interleukin (IL)-1beta and IL-10, but has no significant effect on IL-6. We further investigated the effects of the drug on the major signal transduction pathways associated with inflammation: nuclear transcription factor kappa-B (NF-kappaB) and the mitogen-activated protein (MAP) kinases, extracellular signal regulated kinase, p38 and c-Jun N-terminal kinase (JNK). RAW 264.7 cells were pretreated with 0.625, 1.25 or 5 mg/L avermectin 1 h prior to treatment with 1 mg/L LPS. Thirty minutes later, cells were fixed, and NF-kappaB activation was measured by immunocytochemical analysis, or cells were collected and MAP-kinase activation was measured by western blot. Signal transduction studies showed that avermectin significantly inhibits NF-kappaB p65 translocation into the nucleus and inhibits JNK and p38 phosphorylation protein expression. Therefore, avermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kappaB and MAP-kinase in RAW 264.7 cells.
Article
A double-blind trial in twenty-nine patients with rosacea showed that, after 6 weeks' treatment, metronidazole was therapeutically superior to a placebo (P less than 0-02). It was particularly effective against papules and pustules. The mode of action of metronidazole and other antibiotics in rosacea is not known.
Article
In this review the author after a brief historical note, covers the following topics: incidence, species characteristics, locus of parasites, clinical accounts, histopathology, host parasite interactions, prevention and control and critical problems. Information on other species of demodicid mites is interjected in support of observations on those of man or in instances wherein they offer analogues that could lead to future research.
Article
Demodex folliculorum and D. brevis are redescribed using statistical methods for meristic data and standard generic morphological criteria for all stages. Such data show that these are distinct species. Histological studies indicate that each of these utilizes different niches: D. folliculorum the hair follicle, D. brevis the sebaceous glands. Both species have life cycles consisting of ova, larvae, protonymphs, nymphs, and adults. Population counts of these stages revealed ratios of approximately 3.5:1.5:1.0:1.6:14.6 for D. folliculorum and 8.5:2.6:1.0:3.2:34.7 for D. brevis. The sex ratios (male:female) were 1:4.5 for the former and 1:3.4 for the latter. It is suggested that all host-parasite data obtained since Simon (1842) should be reworked in view of the fact that these two species are found on the same host species, Homo sapiens, and even the same host individual.
Article
Skin biopsy specimens from 4 patients with typical acne rosacea lesions were examined for the presence of T-cell subsets using monoclonal antibodies. The infiltrates consisted chiefly of LEU-1 reactive T cells with a predominance of LEU-3a antibody positive helper-inducer T cells, while LEU-2a staining suppressor-cytotoxic T cells were scarce. These cells penetrated regularly into the follicular wall and the epidermis. The study showed that most T cells in the dermal granulomatous infiltrates around Demodex parts, which were displaced extrafollicularly, were helper-inducer T cells. The predominance of helper-inducer T-cell subsets in the dermal infiltrates of acne rosacea lesions in frequent association with Demodex supports the hypothesis that a cell-mediated immune response plays an important role in the pathogenesis of rosacea.