The significance of Demodex folliculorum density in rosacea

Background Demodex folliculorum has been reported in rosacea in a number of clinical studies. As the Demodex mite is also present in many healthy individuals, it has been suggested that the mite may have a pathogenic role only when it is present in high densities. Moreover, some authors have proposed that a mite density above 5/cm² may be a criterion for the diagnosis of inflammatory rosacea. In this study, the possible role of D. folliculorum and the importance of mite density in rosacea were investigated using a skin surface biopsy technique. Methods Thirty-eight patients with rosacea and 38 age-and-sex-matched healthy subjects entered the study. With the skin surface biopsy technique, we obtained samples from three facial sites. We then determined the mite positivities, the mean mite counts in both study groups, the mean mite densities at each facial site and in the rosacea subgroups, and the mite densities above 5/cm². Results The mean mite count in the rosacea group (6.684) was significantly higher than that in controls (2.868; p < 0.05). The cheek was the most frequently and heavily infested facial region. Ten rosacea patients and five normal subjects had mite densities over 5/cm² ; the difference was not statistically significant (p > 0.05). Conclusions Rosacea is a disease of multifactorial origin, and individual properties may modify the severity of the inflammatory response to Demodex. We suggest that a certain mite density is not an appropriate criterion in the diagnosis of the disease; nevertheless, large numbers of D. folliculorum may have an important role in the pathogenesis of rosacea, together with other triggering factors.     

Clinical and laboratory study of rosacea in northern Greece

Background Numerous factors have been implicated in the pathogenesis of rosacea, which remains obscure. Objectives To examine the epidemiological characteristics of rosacea patients, the histopathological alterations, the prevalence of gastric Helicobacter pylori infection and the role of ultraviolet radiation, to detect the presence of Demodex folliculorum on affected skin and to elucidate the immunological nature of this disorder. Methods The study included 100 patients with rosacea. Each patient was assessed with a clinical, haematological, biochemical and histological examination; serology test for the detection of antibodies against H. pylori; direct immunofluorescence on perilesional, sun exposed skin and indirect immunofluorescence with monkey oesophagus as a substrate; antinuclear antibody titre and a skin surface biopsy to search for Demodex folliculorum. Results Women were more frequently affected. Half of our patients were 51–70 years old. About two‐thirds were phototypes I and II and 73% complained of worsening of conditions after sun exposure. An almost permanent histopathological feature was solar elastosis. Higher prevalence of H. pylori was not established. Prevalence and mean density of Demodex folliculorum were significantly increased in rosacea patients. Direct and indirect immunofluorescence tests were positive in 6.4% and 6.7% respectively. Antinuclear antibody titres were found in 21.1%. Conclusions Our results suggest the pivotal role of chronic sun exposure in the pathogenesis of rosacea. Demodex folliculorum represents a significant cofactor that may contribute to the transition of the disease from a vascular to an inflammatory stage. The low positive results of direct and indirect immunofluorescence do not support a potential autoimmune role in the development of rosacea.     

微生物在玫瑰痤疮中致病机制的研究进展

玫瑰痤疮是一种好发于面中部的慢性炎症性皮肤病,以面部阵发性潮红、持久性红斑、丘疹脓疱等为主要表现,其病因及发病机制尚不清楚.关于微生物在玫瑰痤疮中的致病作用存在争议.微生物一般通过破坏皮肤屏障、诱发炎症反应、分泌生物活性因子及毒素等方式介导玫瑰痤疮的发生.本文总结国内外近年关于微生物与玫瑰痤疮发病的相关研究,进一步揭示...     

Effects of Helicobacter pylori treatment on rosacea: A single‐arm clinical trial study

Rosacea is a chronic dermatological disease. Helicobacter pylori has been discussed as one of its causative factors. In this clinical trial study, we attempted to evaluate the effect of H. pylori standard eradication protocol on the rosacea clinical course. In this single‐arm clinical trial, patients ascertained to have H. pylori infection based on serological studies were assessed to examine existence of rosacea. Patients with concurrent rosacea and H. pylori infection were included in the study and underwent standard H. pylori eradication therapy. Rosacea was evaluated using the Duluth rosacea grading score at the beginning, 2 months later and at the end of the trial (day 180). Of 872 patients positive for H. pylori, 167 patients (19.15%) manifested the clinical features of rosacea. The patients with concurrent rosacea were younger (P < 0.001) and with a female sex predominance (P = 0.03) when compared with rosacea‐free patients. Of 167 patients, 150 received H. pylori eradication therapy, demonstrating a 92% (138/150) cure rate. The rosacea Duluth score grading on day 0, 60 and 180 among 138 patients significantly decreased in most of the criteria except for telangiectasias (P = 0.712), phymatous changes (P = 0.535) and the existence of peripheral involvement (P = 0.431). The present study concluded that H. pylori eradication leads to improvement of rosacea.     

Demodex: a skin resident in man and his best friend

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 generalized 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.     

酒渣鼻发病机制中微生物的作用

酒渣鼻是一种常见的面部慢性炎症性皮肤病,其发病机制尚不明确,其中微生物起重要作用。蠕形螨虫与酒渣鼻发病有密切相关,可能通过Ⅳ型免疫反应致病。在对蠕形螨虫所携带的细菌的研究中,人们发现奥列伦芽胞杆菌、表皮葡萄球菌可能由蠕形螨虫携带,并与之共同致病;幽门螺杆菌、小肠细菌过度生长等可能在合并消化道症状的酒渣鼻发病中起作用,但其相关性和致病机制并不确切。目前尚未发现痤疮丙酸杆菌、沃尔巴克体与酒渣鼻发病有关。     

Risk factors associated with rosacea

Background Although rosacea is a common disease, the cause of disease is still a mystery –Helicobacter pylori infection, genetic predisposition, climatic factors, and detrimental habits are implicated as triggers of rosacea. Objective The aim of current study is to evaluate several suspected risk factors coincidently. Methods Patients with rosacea from a dermatology clinic and skin‐healthy controls from an randomly selected employees' population enrolled the study. Skin status were evaluated by one and same dermatologist. Participants were queried for age, gender, sun‐reactive skin type, and detrimental habits using a questionnaire; blood samples for detecting Helicobacter pylori serostatus were collected. Results Totally 145 skin‐healthy controls and 172 subjects either with flushing episodes or established rosacea included the study. In multivariate analysis, rosacea patients had significantly higher chance to have photosensitive skin types (OR 1.75; 95% CI 1.01–3.04; P < 0.05), positive family history to rosacea (OR 4.31; 95% CI 2.34–7.92; P < 0.0001) or previous smoking status (OR 2.01; 95% CI 1.07–3.80; P < 0.05) comparing with skin‐healthy controls. There were no statistically significant differences either in gender, Helicobacter pylori serostatus, caffeine intake, alcohol consumption, occupational environment, or education level between rosacea patients and controls. Conclusion Rosacea is foremost associated with familial predisposition. There is no association between Helicobacter pylori infection and rosacea in current study.     

Rosacea: I. Etiology, pathogenesis, and subtype classification

Rosacea is one of the most common conditions dermatologists treat. Rosacea is most often characterized by transient or persistent central facial erythema, visible blood vessels, and often papules and pustules. Based on patterns of physical findings, rosacea can be classified into 4 broad subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. The cause of rosacea remains somewhat of a mystery. Several hypotheses have been documented in the literature and include potential roles for vascular abnormalities, dermal matrix degeneration, environmental factors, and microorganisms such as Demodex folliculorum and Helicobacter pylori. This article reviews the current literature on rosacea with emphasis placed on the new classification system and the main pathogenic theories. Learning objective At the conclusion of this learning activity, participants should be acquainted with rosacea's defining characteristics, the new subtype classification system, and the main theories on pathogenesis.     

Association between rosacea severity and relative muscle mass: A cross‐sectional study

Rosacea is thought to be associated with factors involved in metabolic syndrome (MetS). Muscle mass has a beneficial role in preventing MetS, but its link to rosacea remains unknown. We sought to investigate the association between rosacea severity and relative skeletal muscle mass. A cross‐sectional study was conducted on subjects who attended a skin check‐up program at the Kangbuk Samsung Hospital Health Screening Center between 2014 and 2016. Polarized light photographs of the face were taken and evaluated by two dermatologists. Skeletal muscle mass index (SMI, [%] = total skeletal muscle mass [kg] / bodyweight [kg] × 100) was estimated using a bioelectrical impedance analyzer. A logistic regression model was used to evaluate an association between SMI and rosacea. Of 110 rosacea subjects who were finally enrolled, 17 (15.5%) and 93 (84.5%) were classified as having papulopustular and erythematotelangiectatic rosacea, respectively. Categories of SMI comprised the following tertiles: 22.86–38.40%, 38.41–43.44% and 43.45–80.65%. In severity, compared with mild rosacea (75.5%), moderate rosacea (24.5%) incrementally increased as SMI decreased (P_trend < 0.01). Severe rosacea was not observed. After adjustment for age and sex, odds ratios (95% confidence intervals) for moderate rosacea comparing SMI tertiles 1 and 2 to the highest tertile (reference) were 5.66 (1.22–26.20) and 4.43 (1.12–17.55), respectively (P_trend = 0.03). This association was present in women with marginal significance (P_trend = 0.06), but not in men. Relative muscle mass is negatively associated with an increased risk of more severe rosacea, suggesting that skeletal muscle can have a protective effect on rosacea exacerbation.     

玫瑰痤疮发病的免疫机制研究进展

与玫瑰痤疮发生发展有关的因素包括免疫反应、微生物的增多以及神经血管功能失调等。免疫学发病机制涉及固有免疫反应异常,包括皮损处LL-37、KLK5、TLR2表达的增多、炎性体的活化以及肥大细胞的参与等,适应性免疫机制也参与其致病过程,本文对玫瑰痤疮发病的免疫机制研究进展进行综述。     

Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation

The aim of this study is to quantify D. folliculorum colonisation in rosacea subtypes and age‐matched controls and to determine the relationship between D. folliculorum load, rosacea subtype and skin innate immune system activation markers. We set up a multicentre, cross‐sectional, prospective study in which 98 adults were included: 50 with facial rosacea, including 18 with erythematotelangiectatic rosacea (ETR), and 32 with papulopustular rosacea (PPR) and 48 age‐ and sex‐matched healthy volunteers. Non‐invasive facial samples were taken to quantify D. folliculorum infestation by quantitative PCR and evaluate inflammatory and immune markers. Analysis of the skin samples show that D. folliculorum was detected more frequently in rosacea patients than age‐matched controls (96% vs 74%, P < 0.01). D. folliculorum density was 5.7 times higher in rosacea patients than in healthy volunteers. Skin sample analysis showed a higher expression of genes encoding pro‐inflammatory cytokines (Il‐8, Il‐1b, TNF‐a) and inflammasome‐related genes (NALP‐3 and CASP‐1) in rosacea, especially PPR. Overexpression of LL‐37 and VEGF, as well as CD45RO, MPO and CD163, was observed, indicating broad immune system activation in patients with rosacea. In conclusion, D. folliculorum density is highly increased in patients with rosacea, irrespective of rosacea subtype. There appears to be an inverse relationship between D. folliculorum density and inflammation markers in the skin of rosacea patients, with clear differences between rosacea subtypes.     

Relationship between rosacea and sleep

Rosacea is a chronic facial skin disease involved in neurovascular dysregulation and neurogenic inflammation. Behavioral factors such as stress, anxiety, depression and sleep were identified to be associated with other inflammatory skin diseases. Few studies have reported sleep status in rosacea. Aiming to investigate the relationship between rosacea and sleep, a case–control survey was conducted, enrolling 608 rosacea patients and 608 sex- and age-matched healthy controls. Sleep quality was assessed through the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Diagnosis and severity grading of rosacea were evaluated under the standard guidelines of the National Rosacea Society. More rosacea patients (52.3%, n = 318) suffered poor sleep quality (PSQI, >5) than the healthy controls (24.0%, n = 146), displaying a much higher PSQI score (rosacea vs control, 6.20 vs 3.95). There was a strong association between sleep quality and rosacea (odds ratio [OR], 3.525; 95% confidence interval [CI], 2.759–4.519). Moreover, the severity of rosacea was also associated with sleep quality (OR, 1.847; 95% CI, 1.332–2.570). Single nucleotide polymorphisms in hydroxytryptamine receptor 2A and adrenoceptor-β1 genes, which are associated with sleep behaviour, were detected and revealed to be associated with rosacea. Furthermore, the LL-37-induced rosacea-like phenotype and sleep-deprivation mice models were applied, revealing that sleep deprivation aggravated the rosacea-like phenotype in mice, with higher expression of matrix metallopeptidase 9, Toll-like receptor 2, cathelicidin antimicrobial peptide and vascular endothelial growth factor. In conclusion, rosacea patients presented poorer sleep quality, as well as a higher propability of genetic background with sleep disturbance. In addition, poor sleep might aggravate rosacea through regulating inflammatory factors, contributing to a vicious cycle in the progression of disease.     

A randomized, single-blind, placebo-controlled, split-face study with pimecrolimus cream 1% for papulopustular rosacea

Background Rosacea is a common inflammatory skin disorder for which the pathogenesis is unclear. Currently, there is no cure for rosacea, and it seems that standard therapies have focused mainly on minimizing inflammation. Objectives The aim of this study is to investigate the potential efficacy, tolerability and safety profile of 1% pimecrolimus cream for the treatment of rosacea. Methods Twenty‐five patients with papulopustular rosacea were enrolled to a randomized, single‐blinded, placebo‐controlled, split‐face trial of pimecrolimus cream 1% consisting 4 week treatment and 2 week follow‐up period. The patients were instructed to apply first the ‘left side cream’ labelled placebo cream (Ultrabase cream, Intendis GmbH, Berlin, Germany) to the left hemi‐face then the ‘right side cream’ labelled 1% pimecrolimus cream (Elidel; Novartis Pharma, Nuremberg, Germany) to the right hemi‐face, twice daily. They were informed to apply a standard amount of each cream with the fingertip‐unit and not allowed to use any other agent concomittantly other than sunblock. Clinical evaluation and subjective severity assessment were obtained along with photographic documentation at baseline, first, second, and fourth weeks of the therapy and at the follow‐up visit. Rosacea severity score for each sign of erythema, papules, pustules, oedema, and telengiectesia were graded from 0 to 3. Patients were questioned for the subjective symptoms, overall improvement on appearance and side‐effects. Results Twenty‐four patients completed the study with an exceptional compliance and tolerable safety profile. One patient withdrew from the study due to severe flare‐up reaction affecting both hemi‐faces. The mean baseline total rosacea severity scores were 5.06 + 1.29 for both sides and reduced to 2.5 ± 1.06 vs. 3.25 ± 1.24 on pimecrolimus vs. placebo applied sides without the significance (P = 0.06). There was not any significant difference concerning each rosacea sign scores and total rosacea severity scores except for the significant improvement in erythema score and total rosacea severity score obtained on the pimecrolimus‐applied hemi‐face at 2nd week of therapy (P =0.01 and P = 0.03, respectively). The reduction rates of the mean subjective severity scores at 4th week were 49.77% vs. 38.89% for pimecrolimus vs. placebo, respectively, without a statistical significance (P = 0.15). Subjective symptoms responded well in 54.16% of patients concerning pimecrolimus application compared with 12.50% for the placebo application. The side‐effects were mostly transient local irritations. Conclusion Our data implicated that pimecrolimus cream is not superior to placebo except for its efficacy on erythema. We believe that pimecrolimus cream can be a treatment option for rosacea patients with high erythema score for whom an initial accelerated improvement is needed. We believe further studies with topical pimecrolimus cream on larger study groups with different subtypes and severity of rosacea will clarify the potential effect of pimecrolimus cream for the treatment of rosacea.     

Characterization of the facial microbiome in twins discordant for rosacea

Previously, we determined that genetic and environmental factors contributed equally towards rosacea in twins. To assess an environmental factor, we characterized the malar cheek bacterial microbiome from twins discordant for rosacea. We found no significant difference in facial microbiome alpha and beta diversity between related twins discordant for rosacea. However, the relative percentage abundance of Gordonia and Geobacillus, low‐abundant genera, was positively and negatively associated with rosacea severity, respectively. Our data demonstrate a significant correlation between facial microbiome and severity of rosacea in genetically matched twins and importantly that overall microbiome composition is largely unchanged.     

Etiopathogenesis, classification, and current trends in treatment of rosacea

Rosacea is a common chronic dermatosis characterized by varying degrees of flushing, erythema, telangiectasia, edema, papules, pustules, ocular lesions, and phymas. Etiology and pathogenesis of rosacea are still unknown. Many possible causes have been described as inducing the disease or contributing to its manifestation, such as genetic predisposition, abnormal vascular reactivity, changes in vascular mediating mechanisms, Helicobacter pylori infection, Demodex folliculorum infestation, seborrhea, sunlight, hypertension, and psychogenic factors. However, none of these factors has been proved. Rosacea shows a wide spectrum of clinical presentations, which vary over time and with age. Successful management of rosacea requires careful patient evaluation and individualized therapy with appropriate variations and modifications, as the severity of the disorder fluctuates. In mild cases of rosacea, patients are instructed to avoid sun, to apply sun-protective creams, and to avoid facial irritants and other triggers that provoke symptoms. At later stage, drug therapy is often necessary. The disease commonly requires long-term treatment with topical or oral medicaments. Surgical correction may be required for rhinophyma and telangiectasia. We reviewed the current literature on the aspects of the pathogenesis, diagnostic criteria, and treatment options for rosacea.     

Risk of psychiatric disorders in rosacea: A nationwide,population‐based,cohort study in Taiwan

Rosacea has been reported to be associated with psychiatric disorders. Nevertheless, a nationwide study of the relationship between rosacea and comorbid psychiatric diseases in an Asian population has not been conducted. The aim of this study was to clarify the role of rosacea in the various psychiatric disorders by using a nationwide database in Taiwan. Data were obtained from the National Health Insurance Research Database of Taiwan from 2000 to 2013. In total, 7881 patients with rosacea and 31 524 age‐ and sex‐matched controls were enrolled. Patients with rosacea tended to have more coexisting psychiatric disorders. After adjusting for age, sex, comorbidity and residence/regions, the adjusted hazard ratio (HR) of psychiatric disorders for patients with rosacea was 2.761 (95% CI = 2.650–2.877, P < 0.001). Among them, the highest adjusted HR are phobic disorder and obsessive–compulsive disorder of 7.841 (95% CI = 7.526–8.170, P < 0.001) and 6.389 (95% CI = 6.132–6.657, P < 0.001), respectively. The National Health Insurance Research Database of Taiwan does not include the information about rosacea subtypes, severity and laboratory parameters. In conclusion, rosacea is related to various psychiatric disorders. In addition to anxiety and depression, patients are also at increased risk of phobic disorder and obsessive–compulsive disorder.     

Rosacea pathogenesis,common triggers,and dietary role: The cause,the trigger,and the positive effects of different foods

Rosacea is a common chronic inflammatory cutaneous disorder, primarily manifesting on the cheeks, nose, chin, and forehead with a classic relapsing-remitting course that affects mostly fair skin types (Fitzpatrick I and II). The pathogenesis remains unclear, but the complex interplay between environmental and genetic factors may augment the innate immune response and neurovascular dysregulation. Different nutrients may play a role in the pathogenesis of rosacea. Many dietary triggers, including hot beverages, alcohol, spicy foods, caffeine, vanilla, cinnamon, niacin, marinated meats, and dairy products, have been postulated for this disease; however, there is a lack of well-designed and controlled studies evaluating the causal relationship between rosacea and dietary factors. We have explored the available evidence and hypotheses based on trigger-food categories of rosacea, the role of the skin-gut microbiome axis, and potentially benefiting dietary factors such as probiotics, prebiotics, and high-fiber diets.     

Recombinant erythroid differentiation regulator 1 inhibits both inflammation and angiogenesis in a mouse model of rosacea

The erythroid differentiation regulator 1 (Erdr1), which is a novel and highly conserved factor, was recently reported to be negatively regulated by IL‐18 and to play a crucial role as an antimetastatic factor. IL‐18 is a proinflammatory cytokine that functions as an angiogenic mediator in inflammation. Rosacea is a chronic inflammatory skin disorder that is characterized by abnormal inflammation and vascular hyperactivity of the facial skin. To determine whether Erdr1 contributes to the regulation of the chronic inflammatory process in the development of rosacea, an immunohistochemical analysis was performed in healthy donors and patients with rosacea. In this study, we showed that Erdr1 was downregulated, whereas IL‐18 was upregulated, in patients with rosacea, which led us to question the role of Erdr1 in this disorder. Moreover, a rosacea‐like BALB/c mouse model was used to determine the role of Erdr1 in rosacea in vivo. LL‐37 injection induced typical rosacea features, including erythema, telangiectasia and inflammation. Treatment with recombinant Erdr1 (rErdr1) resulted in a significant reduction of erythema, inflammatory cell infiltration (including CD4⁺ and CD8⁺ T cells), and microvessel density with vascular endothelial growth factor (VEGF). Taken together, our findings suggest that rErdr1 may be involved in attenuating the inflammation and angiogenesis associated with the pathogenesis of rosacea. Thus, these results provide new insight into the mechanism involved in this condition and indicate that rErdr1 could be a potential target for therapeutic intervention of rosacea.     

Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy

A standardized skin-surface biopsy (1 cm²) of the cheek was performed in 49 patients with rosacea [13 with erythematotelangiectatic rosacea (ETR). three with squamous rosacea (SR), 33 with papulopustular rosacea (PPR)], and 45 controls. A mean density of 0.7 Demodex folliculorum/cm² was found in controls, 98% of whom had less than five Demodex/cm². When all clinical types of rosacea were considered collectively, the density of Demodex was significantly higher in patients with rosacea than in controls (mean=10.8/cm²: P<0.001). When the various clinical types of rosacea were considered separately. Demodex density was statistically significantly higher than in controls only in the PPR patients (mean=12.8/cm²; P<0.001). The same type of comparison was also made for three other groups of subjects—patients with isolated inflammatory papules (n=4). rhinophyma (n=3), and HIV infection (n=21), respectively: in these groups, the Demodex density did not differ significantly from controls. The present study demonstrates a high density of D. folliculorum in PPR, and supports its pathogenic role in the papulopustular phase of rosacea. The study suggests that standardized surface biopsy could be a useful diagnostic tool for PPR, with a 98% specificity when Demodex density is higher than 5/cm².     

Carotid intima‐media thickness and serum proinflammatory cytokine levels in rosacea patients without cardiovascular risk factors

There is a growing body of evidence linking rosacea to various systemic disorders, even though data regarding the association between rosacea and cardiovascular diseases are presently controversial. We sought to investigate the potential association of rosacea with subclinical atherosclerosis and serum proinflammatory/proatherogenic markers. This study included 44 patients with rosacea and 44 age‐matched and sex‐matched healthy control subjects. Patients with traditional cardiovascular risk factors or a history of cardiovascular events were excluded. Demographic, clinical, and laboratory data, including serum interleukin‐1 beta (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), and high‐sensitivity C‐reactive protein (hs‐CRP) levels were assessed. Carotid intima‐media thickness (CIMT) and carotid plaques were measured by carotid ultrasonography. Serum IL‐1β (P < .001), IL‐6 (P < .001), TNF‐α (P < .001), and hs‐CRP (P < .001) levels were significantly higher in the patient group compared with the control group. Mean CIMT values did not differ significantly between the patient group and control group (P > .05). Patients with moderate to severe rosacea had a significantly greater CIMT than those with mild rosacea (P = .047). Rosacea patients with eye involvement had a significantly greater CIMT than those without eye involvement (P = .008). There was no significant correlation between CIMT values and inflammation parameters. As conclusion, in the absence of other traditional cardiovascular risk factors, rosacea does not seem to affect mean CIMT value. However, specific subgroups such as patients with moderate to severe disease or with eye involvement are associated with increased subclinical atherosclerosis and may require additional attention for cardiovascular disease prevention.