new research on rosacea

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New Research Addresses Rosacea Challenges

Update tracks trending factors changing the treatment landscape.

Recent research on the importance of phenotype classification, comorbidities, triggers, and mechanism of action—including possible implications for metainflammation in coronavirus disease 2019 (COVID-19)—can expand the understanding of rosacea and suggests new directions for diagnosis and prognosis of this widespread skin disease.

Richard Gallo, MD, PhD, chair of the department of dermatology at the University of California San Diego (UCSD), provided an overview of current trends advancing rosacea therapy in his presentation at Maui Derm Live. The in-person dermatology continuing medical education (CME) conference in Hawaii was held concurrently with Maui Derm Connect, a virtual CME conference, from January 25 to January 29, 2021. 1

His remarks were featured in the session, “Update 2021: Acne and Rosacea”, which highlighted new drugs, research, and expert insights into the management of rosacea and acne. Guy Webster, MD, PhD, clinical professor of Dermatology at Thomas Jefferson University, Philadelphia, Pennsylvania, moderated the panel which included speakers Lawrence Eichenfield, MD, vice chair of Dermatology and chief of Pediatric and Adolescent Dermatology at UCSD, and James Leyden, MD, emeritus professor CE of Dermatology at University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Gallo outlined 4 key areas driving change in addressing the challenges of rosacea.

PHENOTYPES MATTER

“Rosacea is now understood by phenotypes,” Gallo said. These phenotypes are (1) diagnostic: fixed centrofacial erythema in a characteristic pattern that may intensify periodically or phymatous changes; (2) major: flushing, papules and pustules, telangiectasia, and ocular manifestations; and (3) secondary: burning sensation; stinging sensation; edema; dryness and ocular manifestations. 2

Gallo stressed the importance of using the phenotype-based classification system for rosacea rather than the subset-based method. Gallo noted limitations in describing a patient’s rosacea through subsets. Often, patients experience many subtypes simultaneously. Categorizing by phenotype allows health care professionals to track patient progress.

COMORBIDITY RISK EXPANDS

“Studies from 2020 confirmed a growing number of rosacea comorbidities including those related to cardiovascular, neurologic, and gastrointestinal risks,” said Gallo. Two meta-analyses found that patients with rosacea have a higher risk of hypertension, CRP, high LDL, epicardial fat, and insulin resistance, Gallo pointed out. According to 8 recent studies that evaluated a total of 200,000 patients, individuals who have rosacea also have an increased risk of migraine, Parkinson disease, and depression. Several studies pointed to higher risks of inflammatory bowel disease.

That is not all. “Innate immune dysfunction drives rosacea’s comorbidities,” said Gallo.

SUN EXPOSURE TOPS TRIGGER LIST

Ultraviolet (UV) light releases potential trigger molecules such a nucleic acids and other damage-associated molecular patterns. Although these endogenous danger molecules released from damaged or dying cells activate the innate immune system by interacting with pattern recognition receptors, they may also promote pathological inflammatory responses.

The cathelicidin peptide LL-37 is another factor. “LL-37 facilitates DNA recognition but does that explain UV sensitivity in patients with rosacea?” asked Gallo. In a study published last year, Gallo and his fellow authors saw results showing that LL-37 amplifies the response to UV products and predicts vascular cell adhesion molecule response in rosacea. 3

MECHANISM OF ACTION

According to Gallo, research on rosacea’s mechanism of action could hold promise for better understanding COVID-19. Mutation scanning identified a possible structure necessary for inflammatory activity relating to COVID-19.”

Disclosure:

Gallo is a co-founder and holds equity interest in MatriSys Bioscience and is a consultant for Sente Inc.

References:

• Webster G. Eichenfield E, Layton J, et al. Update 2021: acne and rosacea. Pre- sented at: Maui Derm For Dermatologists 2021; January 25-29, 2021; Maui, Hawaii.
• Gallo R, Granstein R, Kang et al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;1(78):148-155. doi:10.1016/j.jaad.2017.08.037
• Kulkarni NN, Takahashi T, Sanford JA, et al. Innate immune dysfunction in rosa- cea promotes photosensitivity and vascular adhesion molecule expression. J Invest Dermatol. 2020;40(3):645-655.e6. doi:10.1016/j.jid.2019.08.436

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PracticalDermatology

Rosacea: A Closer Look at the Latest Treatment Options

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When it comes to the topical treatment of rosacea, new treatment options offer the potential to improve outcomes for patients. The latest options for rosacea treatment are based on well-known drugs in novel formulations that optimize outcomes while enhancing tolerability.

Newer Options

Encapsulated benzoyl peroxide cream 5% (Epsolay, Galderma) is a somewhat unexpected treatment for rosacea. The oxidizing agent previously had been tried for the treatment of rosacea but was considered too irritating for use in most patients. However, this novel topical cream formulation for rosacea uses a silica encapsulation process to coat the benzoyl peroxide molecules. The silica shells facilitate slow and deliberate delivery of benzoyl peroxide to the skin.

Encapsulated benzoyl peroxide cream 5% was tested in two 12-week, randomized, double-blind, vehicle cream-controlled phase 3 trials, involving 733 adult subjects with moderate to severe rosacea. 1 Subjects were randomized 2:1 to once daily application of the active cream or vehicle.

The primary outcome measure was the percentage of subjects who achieved Investigator’s Global Assessment score of clear or almost clear. In study 1, 43.5% of active treatment subjects achieved the primary endpoint, and in study 2, 50.1% of active treatment subjects achieved the primary endpoint. This compares to 16.1% and 25.9% of vehicle subjects, respectively. Lesion counts for active treatment were -17.4 and -20.3, respectively, compared to -9.5 and -13.3 for controls, respectively. 1

Of note, there were no treatment-related serious adverse events associated with the cream. Subjects in both the active treatment and the control groups reported similar ratings for local tolerability, suggesting that the encapsulated benzoyl peroxide cream formulation was not associated with notable skin irritation. 1 Furthermore, patients reported that background redness and baseline irritation diminished with use of the formulation.

A long-term, open-label extension study showed that continued treatment with active cream for up to 40 weeks resulted in increased and persistent improvements in IGA scores. Findings indicated a favorable safety and tolerability profile. 2

Topical benzoyl peroxide is just one in a growing class of topical antimicrobials formulated for the treatment of rosacea. Topical antimicrobial medications for rosacea most often are used for their anti-inflammatory properties rather than their bactericidal effects.

Somewhat new to market is topical minocycline foam 1.5% (Zilxi, Journey Medical Corp.), which has been shown to be very effective in controlling rosacea. Interestingly, with use of topically applied minocycline, we typically do not see the side effects that may be seen when the drug is administered systemically. 3 In fact, a maximal use study determined that there is minimal systemic exposure when minocycline foam 1.5% is applied topically. In phase 3 clinical trials, subjects treated with topical minocycline foam 1.5% had significantly greater reductions in inflammatory lesion counts and had higher rates of IGA success, compared to vehicle controls. Active treatment was well-tolerated, and no serious treatment-emergent adverse events were reported. 4

The favorable safety profile of topical minocycline foam 1.5% that was seen in the phase 3 trials was confirmed in a 40-week open-label extension study, in which active treatment was associated with greater than 82% reduction in inflammatory lesions from baseline. A similar proportion of subjects reported being “satisfied” or “very satisfied” with treatment. Local tolerability symptoms improved throughout the study period. 5

For those patients with rosacea who are candidates for oral treatment, low-dose, minocycline extended-release oral capsules (DFD-29, Journey Medical Corp.) show promise. In a phase 2 trial, DFD-29 40mg was associated with statistically significantly higher levels of IGA treatment success (66%) than placebo (11.5%), DEF-29 20mg (31.9%), or doxycycline 40mg (33.3%). Of note, low-dose, minocycline extended-release oral capsules appear to confer benefit without providing an antibiotic effect. In fact, recorded plasma concentrations among treatment patients were below the predicted antimicrobial threshold for the treatment of rosacea. 6

Expanded, Responsible Options

The World Health Organization has identified antimicrobial resistance as a global health threat, and other organizations and professional societies—including the American Acne and Rosacea Society—have echoed the call for antibiotic stewardship. Dermatologists must use topical and systemic antimicrobials responsibly. Relatively new formulations harness the benefits of benzoyl peroxide and minocycline with good tolerability and, more importantly, no or minimal antibiotic action. Hopefully, the anti-inflammatory effects of these agents in specialty formulations can calm the symptoms of rosacea and yield control of the disease without encouraging the development of resistance.

Based in part on a presentation given at DERM2023.

1. Bhatia ND, Werschler WP, Baldwin H, et al. Efficacy and safety of microencapsulated benzoyl peroxide cream, 5%, in rosacea: Results from two phase III, randomized, vehicle-controlled trials. J Clin Aesthet Dermatol . 2023;16(8):34-40.

2. Werschler WP, Sugarman J, Bhatia N, et al. Long-term efficacy and safety of microencapsulated benzoyl peroxide cream, 5%, in rosacea: Results from an extension of two phase III, vehicle-controlled trials. J Clin Aesthet Dermatol . 2023;16(8):27-33.

3. Jones TM, Stuart I. Safety and pharmacokinetics of FMX103 (1.5% Minocycline Topical Foam) in subjects with moderate-to-severe papulopustular rosacea under maximum-use treatment conditions. J Clin Aesthet Dermatol . 2021;14(3):E53-E57.

4. Gold LS, Del Rosso JQ, Kircik L, et al. Minocycline 1.5% foam for the topical treatment of moderate to severe papulopustular rosacea: Results of 2 phase 3, randomized, clinical trials. J Am Acad Dermatol . 2020;82(5):1166-1173. doi:10.1016/j.jaad.2020.01.043

5. Stein Gold L, Del Rosso JQ, Kircik L, et al. Open-label extension study evaluating long-term safety and efficacy of FMX103 1.5% minocycline topical foam for the treatment of moderate-to-severe papulopustular rosacea. J Clin Aesthet Dermatol . 2020;13(11):44-49.

6. Tsianakas A, Pieber T, Baldwin H, et al. Minocycline extended-release comparison with doxycycline for the treatment of rosacea: A randomized, head-to-head, clinical trial. J Clin Aesthet Dermatol. 2021;14(12):16-23.

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Rosacea: New Concepts in Classification and Treatment

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• Published: 23 March 2021
• Volume 22 , pages 457–465, ( 2021 )

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• Esther J. van Zuuren   ORCID: orcid.org/0000-0002-4780-0182 1 ,
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Rosacea is a chronic inflammatory dermatosis mainly affecting the cheeks, nose, chin, and forehead. Rosacea is characterized by recurrent episodes of flushing or transient erythema, persistent erythema, phymatous changes, papules, pustules, and telangiectasia. The eyes may also be involved. Due to rosacea affecting the face, it has a profound negative impact on quality of life, self-esteem, and well-being. In addition to general skin care, there are several approved treatment options available for addressing these features, both topical and systemic. For some features, intense pulse light, laser, and surgery are of value. Recent advances in fundamental scientific research have underscored the roles of the innate and adaptive immune systems as well as neurovascular dysregulation underlying the spectrum of clinical features of rosacea. Endogenous and exogenous stimuli may initiate and aggravate several pathways in patients with rosacea. This review covers the new phenotype-based diagnosis and classification system reflecting pathophysiology, and new and emerging treatment options and approaches. We address new topical and systemic formulations, as well as recent evidence on treatment combinations. In addition, ongoing studies investigating novel therapeutic interventions will be summarized.

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1 Introduction

Rosacea is a chronic inflammatory disease predominantly affecting the centrofacial region (cheeks, chin, nose, and forehead) and the eyes [ 1 , 2 , 3 , 4 ]. Rosacea is characterized by recurrent episodes of flushing, persistent erythema, inflammatory papules/pustules, and telangiectasia. Phymatous changes are infrequent, occurring primarily at the nose (rhinophyma) and more frequently in men [ 1 , 5 ]. More than half of patients with rosacea have ocular features including dryness, foreign-body sensation, photophobia, conjunctivitis, blepharitis, and in rare cases, keratitis that may compromise eyesight [ 1 ]. Rosacea usually starts between 30 to 50 years of age, but can occur at any age [ 1 , 3 ]. Prevalence rates across populations range from < 1 to 22%, but these percentages are likely to be influenced by differences in study design, methodology, population, geographical location, and cultural and social differences in perception of the disease [ 6 , 7 ]. In a recent systematic review, the global prevalence of rosacea was estimated at 5.5% of the adult population. Furthermore, men and women were found to be equally affected [ 8 ], in contrast to previous studies which found a greater prevalence in women [ 1 , 3 ]. Additionally, rosacea is more frequently observed in populations with fair skin of Celtic and northern European descent [ 1 ]. However, in individuals with darker phototypes, rosacea is likely unrecognized and under-diagnosed as erythema and telangiectasia are more difficult to discern [ 4 , 9 ]. Rosacea can lead to embarrassment, low self-esteem, anxiety, depression, and stigmatization. Furthermore, it has an adverse impact on quality of life, social and psychological well-being [ 1 , 10 , 11 ]. Recent studies have reported possible associations of rosacea with increased risk of cardiovascular, gastrointestinal, neurological, auto-immune, and psychiatric disorders along with an increased risk of cancer. Whether these associations have a causal relationship requires further evaluation [ 12 , 13 , 14 ].

In addition to identification and avoidance of patient-specific triggers, self-care advice, and general skin care measures, there are active treatment options available for addressing rosacea features [ 1 , 4 , 5 ]. Approved treatments for erythema include topical brimonidine and oxymetazoline; and for papules/pustules topical ivermectin, metronidazole, azelaic acid, and oral doxycycline 40 mg modified release. Laser and light-based therapies can be used for telangiectasia, erythema, and phyma. The latter may also require surgical correction [ 1 , 4 , 5 ].

This paper reviews the updated knowledge of pathophysiology, the new phenotype-based diagnosis and classification of rosacea (Table 1 ), recent evidence on new combinations of treatments, and new and emerging treatment options (Table 2 ).

2 Pathophysiology

Current inflammatory pathways relevant to rosacea pathogenesis include dysregulation of immune (innate, adaptive, inflammasome) and neurocutaneous mechanisms [ 15 , 16 ]. Genetic susceptibility with modified immune reactivity is suggested by the association of rosacea with single nucleotide polymorphisms in genes associated with the major histocompatibility complex [ 17 ].

Innate and adaptive immune activation may be triggered by microbes including Demodex species and various bacteria including Bacillus oleronius and Staphylococcus epidermidis [ 18 ]. Innate immune activation leads to upregulation of keratinocyte-derived toll-like receptor 2 (TLR2) and proteinase-activated receptor 2 (PAR2). These promote expression of the antimicrobial peptide cathelicidin, which is subsequently activated to bioactive LL-37 by kallikrein 5 (KLK-5) protease, leading to erythema and angiogenesis [ 19 ]. TLR2 facilitates activation of the NLRP3 inflammasome leading to pustule formation, pain, and vascular responsivity via interleukin-1β and tumor necrosis factor-alpha (TNF-α); and prostaglandin E2 release. Furthermore, TLR2 can elicit erythema, telangiectasia, and inflammation via expression of cytokines, chemokines, proteases, and angiogenic factors. PAR2 activation leads to inflammation, pruritus, and pain combined with recruitment of T lymphocytes and neutrophils, degranulation of mast cells, and further release of inflammatory chemokines, cytokines, and prostaglandins [ 15 ]. Adaptive immune system activation, demonstrated by presence of T helper type I (TH1) and T helper 17 (TH17) lymphocytes with their relevant immune mediators, results in increased inflammation and further immune activation [ 20 , 21 ].

Neurocutaneous mechanisms in rosacea—reflecting reactivity to temperature change, exercise, UV, spicy food, and alcohol—may be mediated through transient receptor potential (TRP) ankyrin and vanilloid subfamilies. Specific subfamily receptors may respond to different external triggers leading to release of vasoactive neuro peptides (substance P, pituitary adenylate cyclase-activating peptide, calcitonin gene-related peptide). Sensory nerves also express TLR2 and PAR2 and can perpetuate activation of inflammatory mechanisms [ 22 ].

3 Updated Diagnosis and Classification System of Rosacea

In 2002, the American National Rosacea Society provided a provisional diagnosis and classification system to facilitate communication by using standard criteria between clinicians, researchers, patients, and health and insurance organizations [ 23 ]. In this schema, any of the following primary features in a central distribution on the face was diagnostic for rosacea: flushing (transient erythema), nontransient erythema, papules and pustules, and telangiectasia. Secondary features, which may be present with primary features or appear independently, included burning or stinging sensation, plaque, dry appearance, edema, ocular manifestations, peripheral location, and phymatous changes [ 23 ]. Furthermore, they proposed four presentations called subtypes (erythematotelangiectatic, papulopustular, phymatous, ocular) and one variant (granulomatous). This system has subsequently been widely used for diagnosis, classification, and treatment of rosacea by clinicians and researchers and in the scientific literature [ 2 , 3 , 24 ]. With increased clinical use, shortcomings of this system in diagnosis and classification were increasingly recognized [ 1 , 2 , 3 , 5 , 24 ]. Diagnostic shortcomings were inclusion of features with low predictive value (flushing, papules/pustules, telangiectasia) and exclusion of phyma, of high predictive value. In subtyping, shortcomings included conflation of multiple features into discrete categories that did not accurately represent the presentation of rosacea patients and within which it was impossible to evaluate the relative prevalence of each feature. This fostered a degree of confusion in epidemiological and clinical trial research due to the inability to accurately evaluate key features of interest [ 1 , 2 , 3 , 5 , 24 ]. Consequently, a schema established on patient features that encompassed the diversity of clinical presentations was proposed by the global ROSacea COnsensus (ROSCO) panel in 2017. This phenotype approach was based on an “individual’s observable characteristics that can be influenced by genetic or environmental factors” [ 2 ]. The ROSCO panel represented an international rosacea expert group of dermatologists and ophthalmologists from Asia, Africa, Europe, North America, and South America to ensure global representation [ 2 ]. In this paradigm, subsequently endorsed by the National Rosacea Society [ 3 ], two features were independently diagnostic for rosacea [ 2 ]. In their absence, the presence of two or more major features can establish the diagnosis. Furthermore, minor features might also present with diagnostic and/or major features (Table 1 ). The next step was to align the management strategies with the phenotype approach to enable optimization of patient outcomes and improve general well-being by targeting those features most bothersome to the patient [ 1 , 4 , 25 ].

4 Combination of Treatments

Although combination therapy is common practice among dermatologists and widely recommended, there is only limited evidence supporting its efficacy [ 1 , 4 , 26 ].

4.1 Combination of Topical Metronidazole with Oral Doxycycline 40 mg Modified Release (DMR)

In a randomized, double-blind study with a small sample size ( n  = 72), DMR was combined with topical metronidazole 1% gel once daily in patients with mild to moderate rosacea and compared with topical metronidazole 1% gel once daily [ 27 ]. The combined treatment significantly reduced inflammatory lesions when compared with metronidazole 1% gel monotherapy as early as week 4 and this difference remained significant to week 12 (13.86 lesions vs 8.47; p  = 0.002). Improvements in both IGA and erythema at week 12 were also significantly greater in the combination group indicating that combined treatments can be effective for more than one feature.

Another randomized, double-blind study in 40 rosacea participants compared twice-daily doxycycline 20 mg plus metronidazole 0.75% gel with placebo plus metronidazole 0.75% over 16 weeks [ 28 ]. These results were similar to the study summarized above.

4.2 Combination of Topical Brimonidine and Topical Ivermectin

Topical brimonidine (addressing erythema) and topical ivermectin (addressing inflammatory papules/pustules) are registered for treating rosacea. A randomized, double-blind, vehicle-controlled trial of 190 participants with moderate to severe rosacea (investigator global assessment (IGA) score of 3–4 on a scale of 0–4, higher being worse; having both erythema and inflammatory lesions) evaluated the combination of brimonidine 0.33% gel in the morning and ivermectin 1% cream in the evening [ 29 ]. The first group ( n  = 49) received combination treatment for 12 weeks; the second ( n  = 46) had brimonidine vehicle in the morning and ivermectin 1% cream in the evening for the first 4 weeks, followed by brimonidine 0.33% gel in the morning, and ivermectin 1% cream in the evening for 8 weeks; and the third group ( n  = 95) had brimonidine vehicle in the morning and ivermectin vehicle in the evening.

More participants in the first group (total active) achieved IGA success (clear [0]/almost clear [ 1 ]; overall assessment including background erythema and inflammatory lesions) compared with the third or vehicle group (55.8% vs 36.8%; p  = 0.007). The benefit of brimonidine from the outset with ivermectin (first group) was apparent by week 4 with IGA success in 22.4%; group 2 (the first 4 weeks without brimonidine, only use of ivermectin) in 13%, and vehicle-only group in 9.5%. The reductions in erythema and inflammatory lesions and the self-reported improvement supported the add-on effect of brimonidine gel to ivermectin cream.

4.3 Combination of Topical Ivermectin with Oral Doxycycline 40 mg Modified Release

Topical ivermectin and DMR are registered for treating rosacea, and both address inflammation. One recent phase IIIb/IV, randomized, investigator-blinded trial in 273 participants with severe rosacea (IGA 4) compared ivermectin 1% cream and DMR with ivermectin 1% cream combined with placebo [ 30 ]. After 12 weeks, both regimens resulted in lesion count reduction, but the combination was more effective (80.3% versus 73.6%, respectively; p  = 0.032). Furthermore, combination treatment had a faster onset of action with a difference noted by week 4, and more participants achieved IGA 0 (11.9% vs 5.1%; p  = 0.043) and 100% lesion reduction (17.8% vs 7.2%; p  = 0.006). Both treatment groups also experienced improvements in erythema, stinging, burning, flushing, and ocular signs and symptoms. Few adverse events were reported in both groups.

5 Minocycline

Minocycline is a second-generation, semi-synthetic derivative of tetracycline with both bacteriostatic and anti-inflammatory effects. Minocycline is more lipophilic than the other tetracyclines. The anti-inflammatory effects of tetracyclines include inhibition of metalloproteinases, inhibition of bacterial products that induce inflammation, and inhibition of phospholipase A2. Furthermore, tetracyclines decrease nitric oxide (NO) and inducible nitric oxide synthase (iNOS) (which cause vasodilation) and suppress neutrophil migration and chemotaxis, granuloma formation, and pro-inflammatory cytokine release (such as TNFα, IL-1β and IL-6). Minocycline also has antioxidant capacity by decreasing free radical production and is a potent reactive oxygen species scavenger [ 1 , 31 , 32 , 33 , 34 , 35 ]. Oral minocycline is used off-label in treatment of rosacea but evidence is limited, and there is a small risk of serious side effects with systemic use [ 32 , 36 ].

5.1 Minocycline Foam

The United States Food and Drug Administration (FDA) approved topical minocycline foam 1.5% (FMX103) in May 2020. The foam has been available since October 2020 in the United States. A phase II, dose-ranging, randomized, double-blind trial evaluated the safety, tolerability, and efficacy of minocycline foam (FMX103) for moderate-to-severe papulopustular rosacea [ 37 ]. The study comprised 1.5% and 3% FMX103 and vehicle, involving 232 subjects over 12 weeks. Mean reduction in lesion counts from baseline to week 12 was 21.1 (from baseline mean 34.5) for the 1.5% group, 19.9 (from 34.1) for the 3% group and 7.8 (from 30.6) for vehicle. Reductions with both concentrations of FMX103 were significantly greater than for vehicle ( p  < 0.001). Proportions achieving at least a two-grade improvement in IGA were 41.8% for 1.5% FMX103, 33.3% for 3% FMX103, and 17.9% for vehicle ( p  = 0.002 and p  = 0.032 pairwise comparisons to vehicle respectively). Both doses were safe and well tolerated [ 37 ].

Subsequently, two identical, phase III, randomized, double-blind, vehicle-controlled studies were conducted with 1.5% FMX103 ( n  = 751 and 771) [ 38 ]. Primary efficacy endpoints at week 12 were absolute change from baseline in inflammatory lesion counts, and proportion of subjects with treatment success defined as an IGA score of 0 (clear) or 1 (almost clear) with at least a two-grade reduction. In study I, the reduction in inflammatory lesion counts in the 1.5% FMX103 group was 17.57 (baseline 28.5) versus 15.65 (baseline 29.0) in the vehicle group ( p  = 0.0031), and in study II, corresponding reductions were 18.54 (baseline 30.0) versus 14.88 (baseline 30.2) ( p  < 0.0001). In study I, 52.1% achieved treatment success with the FMX103 1.5% group compared with 43.0% on vehicle ( p  = 0.0273) and in study II, it was 49.1% versus 39.0% ( p  = 0.0077). There were no serious treatment-related adverse events. Most adverse events were mild to moderate, with upper respiratory tract infection being the most common overall, and pruritus being the most common cutaneous adverse event. Head-to-head studies are needed to establish the relative efficacy of topical minocycline in comparison with topical ivermectin, azelaic acid, and metronidazole.

5.2 Minocycline Gel

Still under investigation is minocycline gel. A phase IIb randomized, double-blind, vehicle-controlled trial evaluated the efficacy and safety of 1% and 3% minocycline gel in 270 participants over 12 weeks [ 39 ]. The primary efficacy endpoint was absolute change from baseline in inflammatory lesions at week 12. Secondary endpoints included proportions achieving IGA success for inflammatory lesions (achievement of ‘clear’ or ‘almost clear’ and a two-point reduction in score). Assessments of IGA for lesion severity and erythema (IGAe) were also included and data were collected at each visit regarding safety and tolerability. At 12 weeks, decrease in lesion counts was 12.6 (baseline 24.6) in the minocycline 1% group; 13.1 (baseline 25.1) in the minocycline 3% group, and 7.9 (baseline 24.3) with vehicle. Pairwise comparisons to vehicle were significant ( p  = 0.015 and p  = 0.0073, respectively) and absolute differences in lesion reduction were four to five lesions compared with vehicle. IGA success was achieved in 39% in the minocycline 1% group, 46% in the minocycline 3% group, and 31% in the vehicle group. Only the difference between minocycline 3% and vehicle was statistically significant ( p  = 0.038). IGAe change showed no significant difference between groups. The number of treatment-related adverse events was low: 3% in the minocycline 1% group, 5% in the minocycline 5% group, and 1% in the vehicle group. The authors suggest further evaluation of minocycline gel, which shows comparable results to minocycline foam.

5.3 Oral Low-Dose Minocycline: DFD-29 Extended-Release Capsules

A multi-center, randomized, double-blind, controlled phase II study evaluated the efficacy of DFD-29 extended-release capsules in 205 patients with papulopustular rosacea [ 40 ]. Patients were randomized into four groups: DFD-29 40 mg, DFD-29 20 mg, doxycycline 40 mg, and placebo capsules, once daily for 16 weeks. Treatment success was defined as IGA 0 or 1 with at least a 2-grade reduction from baseline. After 16 weeks, treatment success was highest for DFD-29 40 mg (66%) followed by doxycycline 40 mg (33.3%), DFD-29 20 mg (31.9%) and placebo (11.5%). Furthermore, DFD-29 40 mg resulted in total inflammatory lesion count reduction of 19.2, DFD-29 20 mg of 12.6, doxycycline 40 mg of 10.5, and placebo of 7.3. Quality of life, measured with the RosaQol, improved most in the DFD-29 40-mg group. Common adverse events in all treatment groups were nasopharyngitis and diarrhea. Headache was reported most in the DFD-29 40-mg group (42.3%) compared with the other groups (29–37%). Further evaluation will be needed to confirm these promising results.

6 Encapsulated Benzoyl Peroxide Cream

Benzoyl peroxide is widely used in the treatment of acne in view of its antibacterial properties. Use in rosacea had not been investigated due to prior concern of skin irritation. Encapsulating benzoyl peroxide in silica microcapsules might mitigate irritation and studies were undertaken to assess its effect in rosacea [ 41 ].

A phase II, dose-ranging, randomized, double-blind, vehicle-controlled study with 90 rosacea subjects over 12 weeks demonstrated that 5% encapsulated benzoyl peroxide outperformed 1% benzoyl peroxide cream in achieving treatment success (two-grade improvement in IGA compared with baseline) [ 41 ]. Subsequently, two identical phase III randomized, double-blind, vehicle-controlled trials of micro-encapsulated benzoyl peroxide (E-BPO 5% cream) were conducted ( n  = 361 and 372) in moderate or severe papulopustular rosacea [ 42 , 43 , 44 ]. Subjects were randomized to either active or vehicle once daily for 12 weeks. Primary efficacy endpoints were proportion achieving IGA clear/almost clear (0/1) and absolute change in inflammatory lesion counts. In both trials, the E-BPO 5% cream groups achieved a greater proportion of IGA 0/1 compared with vehicle groups (43.5% versus 16.1% and 50.1% versus 25.9%, respectively). Absolute mean reduction in lesion counts from baseline were 17.4 versus 9.5, and 20.3 versus 13.3, respectively. Most frequently reported adverse events were application-site erythema and pain, mild to moderate in severity. Local tolerability (dryness, scaling, itching, burning/stinging) of E-BPO 5% cream was similar to vehicle. A 52-week, open-label trial for 547 subjects completing the two phase II trials was conducted to evaluate long-term safety and efficacy of E-BPO 5% cream daily [ 45 , 46 ]. Upon attaining an IGA score of 0/1, treatment application was halted but resumed with loss of global success. An IGA score of 0/1 was achieved in 67.2% of the participants. For those who had an IGA of 0/1 at the beginning of this study, mean time to restart treatment was 125 days (mean number of retreatments 1.15). In contrast, those who had an IGA of 1 ‘almost clear’ had a mean time to retreatment of 93 days (mean number of retreatments 1.7) ( p  < 0.05 for both comparisons). While 10 subjects experienced serious adverse events, none were considered related to study treatment. The FDA accepted for review the new drug application of 5% encapsulated benzoyl peroxide cream for rosacea in September 2020. A target action date of April 2021 has been set for the Prescription Drug User Fee Act [ 47 ].

7 Biologics

7.1 secukinumab.

Secukinumab, a human monoclonal antibody registered for treating psoriasis, binds to IL-17A which is involved in the inflammatory process. For papulopustular rosacea, an open-label, rater-blinded, investigator-initiated trial with secukinumab 300 mg weekly for 5 weeks, and then monthly for 2 months was completed in 2019 [ 48 ]. Of 24 patients recruited, 17 completed. Significant reductions at 16 weeks were observed in both papules (median reduction of 5 lesions; p  = 0.01) and global severity score (by 0.3 points on a 0–4 scale; p  = 0.03). However, there was no discussion if these changes were clinically relevant. Improvement in quality of life based on RosaQol was also observed (score reduction by 0.6 points; p  = 0.001), with the same caveat regarding relevance. While the most common treatment-related adverse events were infections, in line with use in psoriasis, no further details were provided. The trialists concluded that randomized controlled trials with larger sample sizes are needed to confirm their findings [ 48 ].

7.2 Erenumab

Erenumab is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and is registered for the prevention of migraine. CGRP is a neuropeptide that modulates nociceptive signaling and vasodilatation. An open-label phase II study to evaluate the efficacy and tolerability of erenumab (AMG 334) 140 mg subcutaneously at a 4-week interval for persistent redness and flushing of rosacea was initiated in June 2020 and is expected to be completed in August 2021 [ 49 ].

7.3 B244 Topical Spray

B244 is a topical spray of a single bacterial strain of Nitrosomonas eutropha (N. eutropha) D23. This bacterium converts ammonia and urea from sweat into nitrite, which has antibacterial properties, and into nitric oxide, which regulates inflammation and vasodilation. B244 in a topical spray for erythema and telangiectasia in rosacea was evaluated in an 8-week, randomized, vehicle-controlled phase II trial. The study was completed in 2019, but no results have been posted [ 50 ].

8 Omiganan Topical Gel

The efficacy and safety of omiganan pentahydrochloride, a synthetic, antimicrobial peptide, in a topical gel was evaluated in four studies in patients with inflammatory lesions in rosacea [ 51 , 52 , 53 , 54 ]. The last study was completed in April 2018 [ 54 ]. However, no results have been published.

9 Rifaximin

Rifaximin is a nonabsorbed, gut-active, oral antibiotic registered for traveler’s diarrhea, irritable bowel syndrome, and hepatic encephalopathy. Associations between rosacea and gastrointestinal disease have been previously described. A study evaluating the role of small intestinal bacterial overgrowth (SIBO) in patients with rosacea demonstrated that eradication of SIBO with rifaximin 400 mg three times daily for 10 days resulted in complete resolution of rosacea features in 78% of patients [ 55 ]. A later pilot study aimed to determine the prevalence of SIBO in patients with rosacea attending a gastroenterology clinic. Half of the 63 patients (51%) were diagnosed with SIBO, compared with 23% of general population controls and 5% of healthy subjects. Patients with rosacea and SIBO received rifaximin 400 mg three times daily for 10 days. Of these, 46% reported clearly or markedly improved rosacea, 25% reported moderate and 11% mild improvement [ 56 ].

A phase II, randomized controlled trial to investigate the safety and efficacy of oral rifaximin delayed-release versus placebo in 236 adults with moderate-to-severe papulopustular rosacea and positive lactulose H2/CH4 breath test started in June 2018 and was to be completed in October 2020, but no results have been posted [ 57 ].

10 DMT210 5% Topical Gel

DMT210 topical gel was developed to downregulate the cutaneous proinflammatory cytokines responsible for the inflammation and redness in rosacea. DMT210 blocks TLR-2 and G-protein coupled receptor signaling, which might inhibit IL-6 and TNF-α expression. The efficacy, safety, and tolerability of twice-daily dosing of DMT210 5% gel in 104 patients with moderate to severe rosacea was evaluated in a 12-week, phase II, multi-center, double-blind, vehicle-controlled trial. The study was completed in April 2018, but no results have been published [ 58 ]. An ophthalmic formulation will also be developed for treating ocular rosacea.

11 Hydroxychloroquine

Hydroxychloroquine is an anti-malaria drug that has been used widely to treat patients with systemic autoimmune diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus). Hydroxychloroquine has an immune-modifying role by reducing pro-inflammatory cytokine production and modulation of certain costimulatory molecules. A recent study in a mouse model of rosacea demonstrated that hydroxychloroquine inhibited pro-inflammatory factors as well as mast cell proteases [ 59 ]. In an additional trial of six adult patients with moderate to severe rosacea treated for 8 weeks with hydroxychloroquine 200 mg twice daily, success rates were 67% for inflammatory lesions (reaching IGA score 0 or 1) and 83% for erythema (reaching a clinician’s erythema assessment [CEA, ranging 0–4] score of 0 or 1) [ 59 ]. There were no adverse events. A recent, multi-center, randomized, double-blind, phase IV pilot study in 66 patients with rosacea (type not specified), compared hydroxychloroquine 200 mg twice daily with doxycycline 100 mg once daily (and a placebo once daily) [ 60 ]. CEA success was defined as a decrease of at least 1 point and IGA success as a score of 0 or 1. Fifty-eight patients completed the 8-week study, and similar improvements were seen in erythema (89.3% for hydroxychloroquine vs 86.7% for doxycycline: p  = 0.193) and papules (82.1% vs 93.3%, respectively; p  = 0.555). In the hydroxychloroquine group, 28.5% of the participants reported adverse events, compared with 33.3% in the doxycycline group. The most common events were dry skin, dry eyes, and dizziness in the hydroxychloroquine group, and dry skin and flatulence in the doxycycline group. However, long-term hydroxychloroquine use can cause irreversible retinopathy, a well-known serious adverse event [ 61 ].

12 Conclusion

Updating the diagnostic approach to rosacea focussing on individual features has led to advances in understanding of pathophysiology, treatment approaches, and ultimately patient care. New treatments for rosacea have been developed in three ways—greater understanding of pathophysiology; development of novel topical modalities for active interventions previously known to be effective in rosacea; and repurposing treatments used in other dermatologic conditions for rosacea. These therapeutic advances expand treatment options and could improve outcomes in rosacea patients. Nevertheless, while achievement of complete or almost complete clearance of rosacea features is the goal, not all patients achieve these outcomes presently, despite treatment adherence. Thus, there is still an ongoing need for more efficacious treatments, including those used in combination, to achieve this outcome. Finally, current treatment approaches have almost exclusively focused on only two features of rosacea—erythema and papules/pustules. Ocular rosacea and phyma, including medical interventions for early inflammatory phases of the latter, have largely been neglected. To comprehensively address the needs of all patients with rosacea, further advances in pathophysiology and treatments are awaited.

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Esther J. van Zuuren

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van Zuuren, E.J., Arents, B.W.M., van der Linden, M.M.D. et al. Rosacea: New Concepts in Classification and Treatment. Am J Clin Dermatol 22 , 457–465 (2021). https://doi.org/10.1007/s40257-021-00595-7

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DOI : https://doi.org/10.1007/s40257-021-00595-7

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Exploring the Link: Trichostasis Spinulosa and Its Association with Early Phymatous Rosacea

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Sechi Andrea , Mariano Luca , Galvan Arturo; Exploring the Link: Trichostasis Spinulosa and Its Association with Early Phymatous Rosacea. Skin Appendage Disord 2024; https://doi.org/10.1159/000540509

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Introduction: Rosacea is a chronic inflammatory skin condition with several clinical subtypes, including phymatous rosacea, which is distinguished by thickened skin, enlarged pores, and irregular surface nodularities, primarily affecting the nose. This manuscript aims to explore the underrecognized connection between early to moderate phymatous rosacea and trichostasis spinulosa (TS), a follicular disorder characterized by the retention of multiple telogen hairs. Methods: A total of consecutive 13 patients with initial phymatous changes and black dilated openings were enrolled. Detailed dermatological assessments, including dermoscopy, were conducted to identify and confirm trichostasis spinulosa. Dermoscopy of the black openings confirmed the presence of hair tufts emerging from dilated follicular openings and plugs. Patients underwent minor procedures using a comedo extractor to remove the hair bundles. Results: All extracted follicular units showed typical characteristics of trichostasis spinulosa, including bundles of telogen hairs surrounded by a sebokeratinous plug. Conclusion: We postulate that the fibrotic processes characteristic of phymatous rosacea may promote the development of TS. Recognizing TS as an early indicator of phymatous rosacea could help prevent disease progression.

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To determine whether you have rosacea, a doctor or other healthcare professional examines your skin and asks about your symptoms. You may have tests to rule out other conditions, such as psoriasis or lupus. Some symptoms of rosacea may be harder to see on brown and Black skin. These include spider veins and flushing. So it's important to pay attention to other symptoms, such as swelling, bumps, facial stinging and dry-looking skin.

If your symptoms involve your eyes, you may see an eye doctor, also called an ophthalmologist, for other tests.

If your symptoms don't improve with the self-care tips below, talk with a member of your healthcare team about a prescription gel or cream. This kind of medicine may help ease symptoms. For more serious rosacea, you might need prescription pills. Laser treatment may be used to reduce flushing and enlarged blood vessels in the face.

How long you need treatment depends on the type of rosacea you have and how serious your symptoms are. Even if your skin calms with treatment, the symptoms often return.

Several medicines are used to help control rosacea symptoms. The type of medicine you are prescribed depends on your symptoms. For example, some medicines or treatments work better for flushing, and some medicines work better for pimples and bumps. You may need to try one or more medicines to find a treatment that works for you.

Medicines for rosacea include:

Gels or other products applied to the skin. For the flushing of mild to moderate rosacea, you may try a medicated cream or gel that you apply to the affected skin. Examples are brimonidine (Mirvaso) and oxymetazoline (Rhofade), which reduce flushing by constricting blood vessels. You may see results within 12 hours after use. The effect on the blood vessels is temporary. Overuse might lead to worse flushing. So rather than using it every day, you might use it only before important events.

Brimonidine and oxymetazoline often aren't covered by insurance.

Other prescription topical products help control the pimples of mild rosacea. Examples are azelaic acid (Azelex, Finacea), metronidazole (Metrogel, Noritate, others) and ivermectin (Soolantra). With azelaic acid and metronidazole, you may not see results for 2 to 6 weeks. Ivermectin may take even longer to improve skin. But the results tend to last longer than they do for metronidazole. Sometimes, using two or more of these products leads to the best results.

• Antibiotic medicine taken by mouth. For more serious rosacea with bumps and pimples, you may be prescribed an oral antibiotic pill such as doxycycline (Oracea, others).
• Acne medicine taken by mouth. For severe rosacea that doesn't respond to other medicine, you may be prescribed isotretinoin (Amnesteem, Claravis, others). It's a powerful oral acne medicine that also helps clear up the bumps of rosacea. This medicine is not to be taken during pregnancy as it can cause birth defects.

Laser treatment

Laser treatment can help improve the look of enlarged blood vessels. It also can help the long-term redness of rosacea. And it often works better than a cream or a pill for this symptom. Because the laser targets visible veining, this method is most effective on skin that isn't tanned, brown or Black.

Talk with a member of your healthcare team about the risks and benefits of laser treatment. Common side effects include redness, bruising and mild swelling for a few days following the treatment. Rare side effects include blistering and scarring. Icing and gentle skin care help while you heal. On brown or Black skin, laser treatment might cause long-term or permanent changes to the color of the treated skin.

The full effect of the treatment might not be seen for weeks. Repeat treatments may be needed to keep the improved look of your skin.

Laser treatment for rosacea is sometimes considered a cosmetic procedure. Such procedures often aren't covered by insurance. However, nowadays some insurances do cover the procedure. Check with your insurance company directly to see if they cover laser treatment for rosacea.

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Lifestyle and home remedies

These self-care tips may help you calm your skin and prevent flare-ups:

• Identify and avoid things that make your symptoms worse. Notice what tends to cause flare-ups for you and avoid those things.

Protect your face. Use a broad-spectrum sunscreen or moisturizer containing sunscreen with an SPF of at least 30, even on cloudy days. Apply sunscreen generously. Reapply every two hours, or more often if you're swimming or sweating.

People with rosacea might benefit from selecting sunscreens that contain titanium dioxide, zinc or both. These are called mineral-based sunscreens or physical sunscreens. Examples include Eucerin Sensitive Mineral Zinc Oxide Protection, La Roche-Posay Tinted Mineral, and others. Or look for products with silicone, such as dimethicone, or cyclomethicone.

Apply sunscreen after you put on any medicine for your face and before applying makeup, if you use it.

Take other steps to protect your face, such as wearing a hat and avoiding midday sun. In cold, windy weather, wear a scarf or ski mask.

Treat your skin gently. Don't rub or touch your face too much. Use a nonsoap cleanser two times a day and moisturize. Some face creams may help reduce redness. Products made for the face that contain azelaic acid, dicarboxylic or niacinamide may help with rosacea symptoms. These products are available without a prescription.

Choose fragrance-free products, and avoid those that contain skin irritants such as alcohol, camphor, urea and menthol.

• Reduce facial symptoms with makeup. Some makeup products may help reduce the facial flushing common with rosacea. For example, green-tinted makeup can help cover up the red color. Avoid alcohol-based gels and thin lotions.

Alternative medicine

Gently massaging your face daily may help ease symptoms of rosacea. Using your fingers, make little circles starting on the center of the face and working to the ears. Do this for a few minutes.

If stress seems to make your symptoms worse, try stress management methods. Examples are deep breathing and meditating.

Coping and support

Rosacea can be distressing. You might feel embarrassed or anxious about how your face looks and become withdrawn or self-conscious. Or you may be upset by other people's reactions. It may help to talk with a counselor about these feelings. It also might help to find a rosacea support group, either in person or online. You may find comfort in connecting with others facing the same types of issues.

Preparing for your appointment

You're likely to start by seeing a member of your primary care team. Or you may be referred to a skin disease specialist, called a dermatologist. If your condition affects your eyes, you may be referred to an eye specialist, called an ophthalmologist.

It's a good idea to prepare for your appointment. Here's some information to help you.

What you can do

Preparing a list of questions helps you make the most of your appointment time. For rosacea, some basic questions are:

• What might be causing the symptoms?
• Do I need tests to confirm the diagnosis?
• What is the best treatment?
• Will this condition go away or is it long term?
• Is there a generic version of the medicine you're prescribing?
• I have other medical problems. How can I manage them together?
• Can I wait to see if the condition clears up on its own?
• What other treatments are there?
• What skin care routine do you suggest for me?

Ask any other questions that come up during your appointment.

What to expect from your doctor

Prepare to answer questions like these:

• When did you first notice your symptoms?
• How often do you have these symptoms?
• Have your symptoms been nonstop or do they come and go?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to bring on or worsen your symptoms?
• Kang S, et al., eds. Rosacea. In: Fitzpatrick's Dermatology. 9th ed. McGraw Hill; 2019. https://accessmedicine.mhmedical.com. Accessed June 13, 2019.
• Soutor C, et al., eds. Acne, rosacea, and related disorders. In Clinical Dermatology: Diagnosis and Management of Common Disorders. 2nd ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 22, 2023.
• Maier LE. Rosacea: Pathogenesis, clinical features and diagnosis. https://www.uptodate.com/contents/search. Accessed May 22, 2023.
• Maier LE. Management of rosacea. https://www.uptodate.com/contents/search. Accessed May 22, 2023.
• AskMayoExpert. Rosacea. Mayo Clinic; 2023.
• Link J (expert opinion). Mayo Clinic. July 10, 2023.
• Feaster B, et al. Clinical effectiveness of novel rosacea therapies. Current Opinion in Pharmacology. 2019; doi:10.1016/j.coph.2018.12.001.
• Soolantra (prescribing information). Galderma Laboratories. 2018. https://www.galderma.com/us/sites/g/files/jcdfhc341/files/2019-01/Soolantra_Cream_PI.pdf. Accessed May 22, 2023.
• Ferri FF. Rosacea. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed June 28, 2023.
• Briggs JK. Facial skin problems. In: Triage Protocols for Aging Adults. Wolters Kluwer; 2019.
• Yousef AB, et al. Assessment of frequency of rosacea subtypes in patients with rosacea: A systematic review and meta-analysis. JAMA Dermatology. 2022; doi:10.1001/jamadermatol.2022.0526.
• Sunscreen FAQs. American Academy of Dermatology. https://222.add.org/media/stats-sunscren. Accessed Jan. 30, 2023.
• AskMayoExpert. Sunburn. Mayo Clinic; 2022.
• Sullivan NA (expert opinion). Mayo Clinic. May 3, 2023.
• Rosacea resource center. American Academy of Dermatology. aad.org/public/diseases/rosacea. Accessed May 22, 2023.
• Kelly AP, et al., eds. Laser treatment. In: Taylor and Kelly's Dermatology for Skin of Color. 2nd ed. McGraw Hill; 2016. https://accessmedicine.mhmedical.com. Accessed May 22, 2023.
• Rosacea on dark skin
• Rosacea on white skin

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Iran is targeting the U.S. election with fake news sites and cyber operations, research says

Iran is stepping up its influence campaign aimed at the U.S., researchers at Microsoft said in a new report , adding to the ongoing efforts by Russia and China to sway American public opinion before the presidential election. 

Researchers identified websites that they attributed to the Iranian operation, aimed at voters on the political left and right. One website, Nio Thinker, bills itself as “your go-to destination for insightful, progressive news and analysis that challenges the status quo” and hosts articles that bash former President Donald Trump and hail Vice President Kamala Harris as “our unexpected, awkward savior.” 

Another site identified by researchers, Savannah Time, poses as a voicey conservative local alt-weekly. “We’re opinionated, we’re noisy, and we’re having a good time,” the about section of the site says. It hosts articles claiming to be written by “the spokeswoman for the International League for Women’s Rights,” arguing for more modest Olympics beach volleyball bathing suits, next to articles lauding Iran’s military might. 

The Microsoft Threat Analysis Center noted the sites were likely using artificial intelligence tools to lift content from legitimate U.S. news publications and repackage articles in a way that hides the content’s source. 

The group behind the sites, according to Microsoft, is part of a larger Iranian operation, active since 2020, that operates more than a dozen other fake news sites targeting English-, French-, Spanish- and Arabic-speaking audiences. The campaign has not found significant success with a U.S. audience, and the sites’ content has not been shared widely on social media, according to the researchers. But researchers say the sites could be used closer to the election. 

Beyond the effort to sow controversy and divide Americans before the vote, researchers said another group linked to the Islamic Revolutionary Guard Corps targeted a “high-ranking official on a presidential campaign” in June with a spear-phishing email from a compromised email account of a former senior adviser and attempted to access an account belonging to “a former presidential candidate.” The report did not name the people who had been targeted. 

Iran’s United Nations mission did not immediately respond to a request for comment but denied the reports of meddling in a statement to The Associated Press : “Iran has been the victim of numerous offensive cyber operations targeting its infrastructure, public service centers, and industries. Iran’s cyber capabilities are defensive and proportionate to the threats it faces. Iran has neither the intention nor plans to launch cyber attacks. The U.S. presidential election is an internal matter in which Iran does not interfere.”

Microsoft’s report also noted continued activity by Russia, including an operation by a group researchers call Storm-1516 , which produces propaganda videos in support of Trump and Russian interests and distributes them through a network of fake news websites connected to a former U.S. police officer. China-linked actors, the report said, had also pivoted increasingly to spreading propaganda via video and had leveraged a network of online accounts to stoke outrage around pro-Palestinian university protests. 

The researchers reported an expectation that Iran, along with China and Russia, would intensify cyberattacks against candidates and institutions and increase efforts to divide Americans with propaganda and disinformation in the run-up to the election.

Brandy Zadrozny is a senior reporter for NBC News. She covers misinformation, extremism and the internet.

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AI Can Detect Pediatric Eye Diseases From Mobile Photographs

Edited by Manasi Talwadekar

August 08, 2024

Artificial intelligence (AI) can detect eye diseases in children with high accuracy using mobile photographs.

METHODOLOGY:

• This cross-sectional study, conducted at Shanghai Ninth People's Hospital in China from October 1, 2022, to September 30, 2023, involved 476 children diagnosed with myopia (n = 251), strabismus (n = 180), and/or ptosis (n = 171).
• The researchers used 1419 images taken using a smartphone to train a model based on deep learning.
• They assessed the sensitivity, specificity, and accuracy of the model.
• The model showed high sensitivity and correctly identified myopia, strabismus, and ptosis in 84%, 73%, and 85% of cases, respectively.
• It also correctly identified individuals without myopia, strabismus, and ptosis (specificity: 76%, 85%, and 95%, respectively).
• The model showed good accuracy (80%-92%) and high performance (83%-94%) for all three conditions.

IN PRACTICE:

"These results suggest that it can assist families in screening children for myopia, strabismus, and ptosis, facilitating early identification and reducing the risk of visual function loss and severe problems due to delayed screening," the authors wrote.

The study was led by Qin Shu, MD, of the Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Jiali Pang, MS, of the Shanghai Artificial Intelligence Laboratory, Shanghai; and Zijia Liu, PhD, of the Institute of Image Communication and Network Engineering at Shanghai Jiao Tong University, Shanghai. It was published online on August 6, 2024, in JAMA Network Open .

LIMITATIONS:

The single-center design and small sample size of the study may limit the generalizability of the findings. Only one photograph per participant was used, which may restrict the capabilities of the algorithm. The sample sizes for the three conditions varied, potentially affecting the sensitivity of the model in detecting strabismus.

DISCLOSURES:

The study was supported by the National Natural Science Foundation of China; Shanghai Science and Technology Innovation Action Plan Biomedical Technology Support Special Project; Target Commission of China Hospital Development Institute, Shanghai Jiao Tong University; Shanghai Jiao Tong University School of Medicine High Peak Plateau Double Hundred People Plan; Shanghai Rising Stars Young Medical Talents Cultivation Program; Shanghai Municipal Commission of Health Excellence Research Program; and the Undergraduate Training Program on Innovation, Shanghai Jiao Tong University School of Medicine. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Send comments and news tips to [email protected] .

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New insights into rosacea pathophysiology: a review of recent findings

Affiliation.

• 1 Department of Dermatology, University of California, San Francisco, California. Electronic address: [email protected].
• PMID: 24229632
• DOI: 10.1016/j.jaad.2013.04.045

Rosacea is a common, chronic inflammatory skin disease of poorly understood origin. Based on its clinical features (flushing, chronic inflammation, fibrosis) and trigger factors, a complex pathobiology involving different regulatory systems can be anticipated. Although a wealth of research has shed new light over recent years on its pathophysiology, the precise interplay of the various dysregulated systems (immune, vascular, nervous) is still poorly understood. Most authors agree on 4 major clinical subtypes of rosacea: erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea. Still, it needs to be elucidated whether these subtypes develop in a consecutive serial fashion or if any subtypes may occur individually as part of a syndrome. Because rosacea often affects multiple family members, a genetic component is also suspected, but the genetic basis of rosacea remains unclear. During disease manifestation and early stage, the innate immune system and neurovascular dysregulation seem to be driving forces in rosacea pathophysiology. Dissection of major players for disease progression and in advanced stages is severely hampered by the complex activation of the innate and adaptive immune systems, enhanced neuroimmune communication, profound blood vessel and possibly lymphatic vessel changes, and activation of almost every resident cell in the skin. This review discusses some of the recent findings and aims to build unifying hypotheses for a modern understanding of rosacea pathophysiology.

Keywords: AMP; CAMP; CCL2; CXCL8; ER; ETR; H2R; HTR3A; Histamine receptor-3; IL; KLK; MMP; NF-κB-C/EBPa; NK; Nuclear factor-kappa-B-C/EBPa; PACAP; PPR; PhR; SP; Serotonin receptor-3A; TGF; TLR; TRP; TRPA1; TRPV; TRPV1; Th1; UV; VEGF-A; adaptive immunity; antimicrobial peptide; antimicrobial peptides; cathelicidin antimicrobial peptide; cysteine-X-cysteine chemokine-8; cysteine-cysteine chemokine-2; cytokines; endoplasmic reticulum; erythematotelangiectatic rosacea; fibrosis; innate immunity; interleukin; kallikrein; mast cells; matrix metalloproteinases; natural killer; neurovascular system; papulopustular rosacea; phymatous rosacea; pituitary adenylate cyclase activating polypeptide; substance P; toll-like receptor; transforming growth factor; transient receptor potential channel; transient receptor potential channel ankyrin receptor 1; transient receptor potential channel vanilloid receptor 1; transient receptor potential ion channel vanilloid type; type 1 helper T cell; ultraviolet; vascular endothelial growth factor-A.

Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

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• [Current insights into the pathophysiology of rosacea]. Schauber J, Homey B, Steinhoff M. Schauber J, et al. Hautarzt. 2013 Jul;64(7):481-8. doi: 10.1007/s00105-012-2516-7. Hautarzt. 2013. PMID: 23760500 Review. German.
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7 F-Rated Growth Stocks to Avoid Like the Plague in August 2024

InvestorPlace - Stock Market News, Stock Advice & Trading Tips

What do you call a growth stock that isn’t growing any more?

The answers are many. You can call it a disappointment. A drain on your portfolio. A bad investment. Any of these are true of F-rated growth stocks , as evaluated by the Portfolio Grader.

And in today’s market, you can ill-afford to a bad investment. The market is in some turmoil this summer.

I know it’s only temporary, but times like these are when some investors start to panic and make bad decisions – particularly when they see their hard-earned money start to drain away in a sell-off.

It can be tempting to take a flyer on a stock in a weakened position. In fact, sometimes that can be a very good decision to buy strong growth stocks at a discount.

You also need to be able to identify those opportunities rather than F-rated growth stocks that have little, if any, hope of bouncing back in the near future.

F-rated growth stocks are typically characterized by weak fundamentals, poor financial health, and inconsistent performance, which can lead to substantial losses.

They can also be volatile, with extreme price fluctuations driven by speculation rather than solid financial performance.

We’re using the Portfolio Grader today to help us identify the worst growth stocks available today, based on factors such as analyst sentiment, growth history, earnings reports and momentum. All of these names are on my list of stocks to avoid today.

Chinese EV maker  Nio  (NYSE: NIO ) has to be one of the most disappointing electric vehicle stocks. I had high hopes at one point that Nio’s battery-swapping technology would be a difference-maker and would allow Nio to become a dominant EV company in Asia.

But not any longer. It’s hard to have faith in any company that used to trade for $60 a share and now is down closer to $3.

Nio has had a lot of starts and stops. It’s getting ready to launch its new mass market EV brand, Onvo, with the first Onvo model, the L60, to debut in September.

There’s also a lot of competition in the Chinese EV space, and Nio will likely be shut out by cars that are selling at a lower price point than the L60, which has a pre-order price of $30,460.

Nio reported delivering 20,498 vehicles in July, which is the third consecutive month that the company delivered more than 20,000 vehicles. But the market is obviously not impressed, as NIO stock is down 60% this year and 33% in the last three months.

Nio gets a “D” rating for growth and an “F” rating overall in the Portfolio Grader.

FuelCell Energy (FCEL)

FuelCell Energy (NASDAQ: FCEL ) manufactures, operates and services Direct Fuel Cell power plants that produce hydrogen. For providers who are looking for a green energy solution, hydrogen is appealing because it produces zero carbon emissions.

It has the potential to be highly efficient in fuel cells by providing more energy per unit of fuel compared to traditional combustion engines.

The company has more than 100 fuel cell plants in operation around the world and has generated more than 15.8 million megawatt-hours of power.

But just because it sounds like a good idea doesn’t make something a good investment. Second-quarter revenue was $22.4 million, down from $38.3 million a year ago. FuelCell Energy posted a loss of $7.1 million, or 7 cents per share.

Obviously, growth is not in the cards for FuelCell, despite its efforts to expand its business in the Koren market. There are much better opportunities for investors.

FCEL stock is down 71% so far this year. It gets “F” ratings for growth and overall in the Portfolio Grader.

Mullen Automotive (MULN)

Tell me if you’ve heard this one before – Mullen Automotive (NASDAQ: MULN ) stock is below $1 per share again.

This is a sad repeat of a story that’s plagued the EV company for the last several months. Mullen actually enacted three reverse stock splits last year, including a 1-for-100 split in December, in a desperate ploy to keep the stock price over $1 and maintain compliance with Nasdaq listing rules.

The cumulative ratio of all these stock splits are 1-for 22,500. And more dilution is on the way, as Mullen announced plans to resell up to 85 million shares on the conversion of notes and exercise of warrants.

When Mullen made the announcement there were only 24.85 million shares outstanding. Mullen acknowledged that the transactions could lead to “substantial diminution to the value of shares of common stock held by our current stockholders.”

Mullen only invoiced for 362 vehicles in six months ending March 31. It posted a net loss of $235 million in that period, while invoicing only $16.3 million.

Mullen stock is trying to make deals to turn things around, but another reverse stock split seems inevitable. MULN stock is down 95% this year and earns a “C” rating for growth and an “F” rating overall in the Portfolio Grader.

SolarEdge Technologies (SEDG)

SolarEdge Technologies (NASDAQ: SEDG ) is another green power company. It makes power optimizers and inverters to help solar panels operate more efficiently.

The primary issue for SolarEdge, however, isn’t the quality of its work or the efficiency of its equipment. It’s the overall economy that makes solar power investment less appealing right now.

Interest rates remain inflated and the Fed seems stubbornly opposed to providing relief. Solar panels are a significant expense and fewer people are willing to borrow money to convert their homes to solar as long as interest rates remain high.

Revenue in the second quarter was $265.4 million, down 73% from a year ago. The company posted a net loss of $130.8 million, a year after posting a profit of $119.5 million.

If interest rates drop, then SolarEdge may return to its growth ways. But that’s not happening now. SEDG stock is down 75% this year and gets “F” ratings for growth and overall in the Portfolio Grader.

2U (NASDAQ: TWOU ) is an educational technology company that works with nonprofit colleges and universities to create online degree and nondegree programs. But it hasn’t been a great business model, as many colleges are able to offer online courses without outside help.

The Maryland-based company filed for Chapter 11 bankruptcy in July, after reporting more than $1 billion in debt in the first quarter and only $125 million in cash.

2U announced a deal with  lenders to cut its debt by 50% , while extending the duration of its loan. It will also receive an additional $110 million in capital from lenders.

TWOU stock is down 95% this year and is approaching $1 per share despite instituting a 1-for-30 reverse stock split this summer. The stock is one to avoid.

TWOU gets “F” ratings for growth and overall in the Portfolio Grader.

Dermata Therapeutics (DRMA)

Dermata Therapeutics (NASDAQ: DRMA ) is a clinical-stage biotechnology company based in California. Dermata is focused on creating treatments for skin conditions and diseases.

Its lead drug candidate, DMT310, is in Phase 3 trials for the treatment of acne, rosacea, and psoriasis. It is a once-weekly topical product made from naturally sourced freshwater sponges. DMT310 has been studied for the treatment of acne, rosacea, and psoriasis.

The company says it’s enrolled more than 50% of its patients in the trial and hopes to complete enrollment in the second half the year.

The challenge with biotech companies, of course, is that research and development is expensive and companies don’t have a revenue stream during the long testing process. Companies are reliant on raising money and acquiring partners during the testing until they can bring a drug to market and start gaining revenue.

For the second quarter, Demata reported having $4.9 million in cash on hand, down from $7.4 million in the previous quarter. The company spent $4.8 million during the quarter on research and company operations, and raised $2.3 million from selling warrants.

The company believes it has sufficient funds to operate into the fourth quarter, so it will have to raise additional money if its going to continue its work.

DRMA stock is down 75% this year and gets a “C” rating for growth and an “F” rating overall in the Portfolio Grader.

Plug Power (PLUG)

Plug Power  (NASDAQ: PLUG ) had another bad day this week, as the company posted another disappointing earnings report that missed analysts’ expectations for both revenue and earnings per share.

The company, which is attempting to build the first commercially viable market for hydrogen fuel cell technology, posted revenue of $143.3 million for the second quarter, down from $260.1 million a year ago.

The company also posted another big operating loss of $244.6 million slightly worse than the $233.8 million loss that Plug sustained in the second quarter of 2023. Overall, Plug’s loss came in at 36 cents per share.

Even though Plug has deployed more than 69,000 fuel cell systems and more than 250 fueling stations, I wouldn’t call what its doing a viable business. At some point you need to start making money, and Plug isn’t anywhere close.

Plug is projecting full-year revenue this year to be between $825 million and $925 million. A year ago it posted revenue of $891 million, so it appears growth this year will be challenging at best.

PLUG stock is down 54% this year and gets “F” ratings for growth and overall in the Portfolio Grader.

On the date of publication, neither Louis Navellier nor the InvestorPlace Research Staff member primarily responsible for this article held (either directly or indirectly) any positions in the securities mentioned in this article. The opinions expressed in this article are those of the writer, subject to the InvestorPlace.com Publishing Guidelines .

On the date of publication, the responsible editor did not have (either directly or indirectly) and positions in the securities mentioned in this article.

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Regents announce Suresh Garimella as U of A presidential candidate

Suresh Garimella

The Arizona Board of Regents announced today that Suresh Garimella , president of the University of Vermont, is a candidate for the position of 23rd president of the University of Arizona.

As president of the University of Vermont, Garimella more than doubled the university's research enterprise and strengthened state and community relationships. Garimella is a professor of mechanical engineering and a highly cited scholar and researcher, who has continued to focus on teaching and mentoring students as president, annually leading an undergraduate seminar class in civil discourse and continuing to supervise Ph.D. students. 

Prior to his time at UVM, Garimella was executive vice president of research and partnerships and a distinguished professor at Purdue University, where he helped build the university's research enterprise and online footprint and diversified its funding sources.   

The board will interview Garimella on Friday, Aug. 9, from 7-9 a.m. After the interview in executive session, the board may reconvene in public session, which will be  available via livestream and posted on  the board's YouTube channel in the following days. 

"The board and search committee were impressed by the exceptional caliber of prospects aspiring to lead the University of Arizona into a new era of excellence," said ABOR Chair Cecilia Mata, who served on the search committee. "After a thorough search process, Dr. Garimella displays the visionary leadership qualities and a record of distinguished scholarship necessary to lead the U of A into its next chapter."  

The U of A Search Advisory Committee has met numerous times over the last five months, vetting all presidential prospects, informed by feedback provided by the community. Throughout the search, ABOR and the search committee  engaged community members and stakeholders during 19 listening tour sessions, dozens of individual meetings, three public town halls, and through emails and a campuswide survey, resulting in feedback from more than 4,200 students, employees and community members. In addition, search committee members have connected with their networks and constituencies throughout the process.   

"It has been a joy to represent the U of A during the search for our next president, and I'm delighted by the collaboration and consideration of ABOR and my colleagues on the search committee," said presidential search committee   member Joellen Russell , U of A Distinguished Professor of Geosciences. "We ended with a deep pool of amazing prospects, and I'm so pleased Dr. Garimella has accepted an interview with ABOR. As a sitting president of a fellow land-grant university and eminent scholar, his interest in this job means that he sees the potential and strength of this multicultural powerhouse in the desert that is the University of Arizona."  

University President Robert C. Robbins announced in April that he would step down after fulfilling the terms of his current contract, set to end in June 2026, or before that if ABOR were to name a successor sooner. 

Additional information about the U of A presidential search can be found on the ABOR website , and comments on the search may be sent to  [email protected] . 

Additional information:

• Learn more about Garimella
• Presidential search community feedback  
• Presidential Search Advisory Committee
• Arizona Board of Regents YouTube channel

Resources for the Media

ABOR Media Relations [email protected]

Going for gold: U of A's Delaney Schnell among several Wildcats heading to Paris Olympics

By the numbers: 12 things to know about Arizona's move to the Big 12

U of A joins STARS College Network to boost support for prospective students from rural areas

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University of arizona in the news.

The Washington Post Thursday Dogs can smell human stress, and it bums them out, study shows

The Washington Post Thursday Can you tell which sport is which? Paris Olympics symbols go avant-garde.

The Washington Post Thursday Sponge vs. dishcloth: Which one is grosser?

The New York Times Tuesday Hurricane scale alone can't account for a storm's destruction

National Geographic Tuesday Apollo moon rocks reveal secrets of the moon's thin 'atmosphere'

Reports on Completed Research

As results of Society-funded studies are presented or published, we will post results on this page.

• Association found between rosacea and ulcerative colitis  
• Ros-NET: new computer-aided rosacea diagnostic tool poses promising advance  
• LL-37 modulates mast cell calcium influx  
• Characterization of the facial microbiome in twins discordant for rosacea  
• A novel therapeutic approach via modulation of sphingolipid signaling in rosacea
  
• The role of mast cells in rosacea inflammation  
• Factors that affect rosacea: A cohort-based study on twins  
• Norepinephrine and adenosine-5’-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells  
• Kallikrein protease inhibitors in the pathogenesis of rosacea  
• Functional role of PACAP and its receptors in neurovascular aspects of rosacea  
• Cellular and molecular analysis of transient receptor potential (TRP) ion channels and neurovascular regulation in rosacea patients  
• Role of skin sympathetic nerve activity in rosacea  
• Clinical and molecular analysis of differences between rosacea and photoaging  
• Role of beta-arrestin in cutaneous flushing  
• Rosacea prevalence and relationship to cutaneous photodamage  
• Role of proteases and endothelin-converting enzyme in rosacea  
• Structural and biological changes in rosacea skin induced by the 595nm long-pulse dye laser and intense pulsed light  
• Mite-related bacteria may induce rosacea inflammation  
• Cell biologic effects of ATP on endothelial cells  
• Allergy-like reaction may trigger inflammation in rosacea  
• Role of serine proteinases and proteinase-activated receptors (PAR-2 and PAR-4) in the pathophysiology of rosacea  
• Glycomics analyses of tear fluid for the diagnostic detection of ocular rosacea  
• Effects of neuropeptides and sebocyte-derived factors on human dermal microvascular endothelial cells in the skin: A possible mechanism for the development of vascular and inflammatory lesions in rosacea  
• Experimental studies in the pathogenesis of rosacea  
• A bioengineering evaluation of facial rosacea  
• Perceptions of self in persons with rosacea  
• The role of bacterial antigen(s) in the etiology and persistence of papulopustular bacteria  
• The role of nitric oxide in rosacea  
• Immune system may trigger onset of rosacea symptoms  
• Influence of skin temperature on bacteria in rosacea  
• Endoglin expression in dermal endothelial cells  
• The role of vascular endothelial growth factor in rosacea  

Association found between rosacea and ulcerative colitis Dr. Hester Lim, a postdoctoral research fellow in dermatology at Johns Hopkins University School of Medicine.

In a new NRS grant-funded study, researchers have found that ulcerative colitis, a type of digestive disorder, is two times more likely to be present in individuals with rosacea compared to those without rosacea.

Drs. Hester Gail Lim and Anna Chien at Johns Hopkins University Medical Center compared the incidence of gastrointestinal disease from the records of 1,104 individuals with rosacea from Johns Hopkins Hospital from 2013 to 2016 with a control group of 5,937 individuals without rosacea, adjusting for other factors including age, gender, ethnicity and smoking. The risk of gastrointestinal disease in general was not different between rosacea patients and those without rosacea.

Ulcerative colitis is a subtype of inflammatory bowel disease (IBD) and is characterized by a variety of symptoms, including diarrhea, bloody stools, weight loss, fever and abdominal pain. The condition is relapsing, with bouts of improvement and flares, and left untreated, severe forms may lead to life-threatening complications.

The investigators wrote that there are complex reasons as to why individuals with rosacea are more likely to develop an IBD, or vice versa. The digestive tract, like the skin, is exposed to environmental factors, they noted, and the complex interplay between exposure and a person’s genetic risk is believed to cause changes in the immune system that may cause the immune system to mistakenly target both the gut in IBD and the skin in rosacea. This in turn may lead to both long-term on-and-off inflammation of the gut lining, particularly the colon, and recurring skin symptoms in those with rosacea. Antibiotics, which are often given to individuals with rosacea and have themselves been linked to digestive disorders in other studies, did not appear to affect the association between rosacea and gastrointestinal disease, they said.

The researchers noted that other medical studies have supported their findings on rosacea and IBD and have reported on different aspects of the relationship between the two disorders — for example, that the connection between rosacea and IBD is stronger in those under 30 years of age and in men and that the relationship is stronger when the individuals have IBD rather than rosacea initially.

Ros-NET: new computer-aided rosacea diagnostic tool poses promising advance Dr. Benjamin Kaffenberger, assistant professor of dermatology at the Ohio State University

An NRS-funded study found that a computer-assisted rosacea analysis tool offers the potential to improve the visual assessment practices that dermatologists use to evaluate the disorder. This initial research increases the possibility that doctors and rosacea sufferers may one day have access to technology that is less subjective and less variable than today’s most common diagnostic methods.

Led by Dr. Benjamin Kaffenberger, the team of six researchers at the Ohio State University’s Department of Dermatology and the Wake Forest School of Medicine collected images, clinical findings and demographics on 166 rosacea patients, as well as three to five photographic angles of each patient. The researchers initially set out to build an algorithm similar to one they had previously developed for acne, but thanks to advances in computing technology, they were able to use artificial intelligence to create a “deep learning” algorithm specifically focused on rosacea.

The algorithm, dubbed “Ros-NET,” relies on digital images shot in natural white light, and does not require assistance in locating areas affected by rosacea. Instead, the algorithm uses natural facial features to determine facial boundaries, and lighting features to identify rosacea prone areas. The researchers used more than 1 million patient images from existing databases to train and refine the algorithm’s detection capabilities.

The Ros-NET system was able to accurately identify rosacea 88-90% of the time. However, researchers noted that the current framework cannot determine the types of symptoms or lesions, nor can it describe the affected areas in detail. Further work on the algorithm should help improve on these factors, they said.

The scientists observed that the greatest needs in future development of computer-aided rosacea diagnosis are additional patient images and greater identification accuracy, which may include the use of a greater diversity of patient images, skin types, rosacea types and varied severities.

Publication of results: Binol H, Plotner A, et al. Ros-NET: A deep convolutional neural network for automatic identification of rosacea lesions. Skin Res Technol 2020 May;26(3):413-421. doi:10.1111/srt.12817

LL-37 modulates mast cell calcium influx Dr. Anna Di Nardo, associate professor of medicine at the University of California-San Diego.

In earlier research, Dr. Anna Di Nardo, professor of medicine at the University of California-San Diego, and colleagues found that cathelicidins, an antimicrobial peptide involved in immune responses that is overproduced in people with rosacea, activate mast cells and induce inflammation in rosacea skin. In this subsequent study, Dr. Di Nardo’s team more closely investigated how mast cells interact with nerve cells, attempting to further understand mast cells’ role as the crossroads connecting the immune and nervous system reactions responsible for rosacea flare-ups.

Working with mice, researchers first tested whether treating mast cells with cathelicidins increased their production of neuropeptides that induce nerve cells to produce the proteins that communicate inflammation between cells. Contradictory to their hypothesis, they found that this did not occur. However, when nerve cells were treated with cathelicidins directly, this did trigger a reaction and slightly increase the release of neuropeptides.

Next, the research team treated mast cells with the neuropeptides produced by nerve cells as a result of cathelicidin exposure, and found that the mast cells’ protein receptors showed increased activity, producing the pro-inflammatory response seen in rosacea flare-ups.

The investigators concluded that sensory nerves can activate mast cells through the release of neuropeptides. However, they were unable to confirm direct release of neuropeptides as a result of cathelicidins triggering sensory nerves. As a result, Dr. Di Nardo’s team now hypothesizes that external stimuli activate sensory nerves, causing the release of neuropeptides which induce cathelicidin production in mast cells, activate sensory protein receptors and initiate the inflammatory response seen in rosacea flare-ups.

Characterization of the facial microbiome in twins discordant for rosacea Dr. Daniel Popkin, assistant professor of dermatology at Case Western Reserve University

Dr. Popkin and colleagues at Case Western Reserve University found a significant correlation between the severity of rosacea and facial bacterial dysbiosis – an imbalance in the mix of bacteria, fungi and viruses that are normal inhabitants of the healthy face – potentially providing a basis for future research into what causes rosacea and how to treat it

The scientific investigators studied 60 individuals, of whom 42 were healthy subjects and 18 had rosacea. The study participants were recruited at the annual Twin Day Festival in Twinsburg, Ohio. The investigators noted that studying the role of the microbiome in rosacea patients may be important because microbial dysbiosis could be associated with the pathogenesis of rosacea as well as with its comorbidities. This possibility was suggested because both rosacea and many of its comorbidities – diseases that have been reported to occur at the same time as rosacea – are involved with the skin and other barrier tissues that host a wide variety of bacteria and other microflora. In addition, the researchers noted they had the advantage of studying both identical and fraternal twins, whose genetic and environmental similarities make their study factors easier to evaluate.

Their results aligned with earlier studies that showed there was less bacterial diversity when skin disease was present, they said, though the relationship was not statistically significant. However, they did find that a 10% increase in the relative percentage of bacteria from the genus Gordonia or a 10% decrease in the relative percentage of bacteria from the genus Geobacillus was significantly predictive of a higher NRS severity score.

Because the researchers were unable to identify differences beyond the genus level – a biological rank above the more specific term species but under the less specific term family – further study will be needed to determine which species may be involved.

Publication of results: Zaidi AK, Spaunhurst K, Sprockett D et al. Characterization of the facial microbiome in twins discordant for rosacea. Exp Dermatol 2017 Dec 28. doi: 10.1111/exd.13491.

A novel therapeutic approach via modulation of sphingolipid signaling in rosacea
 Dr. Yoshikazu Uchida, research dermatologist, and Dr. Peter Elias, professor of dermatology at the University of California-San Francisco

Dr. Yoshikazu Uchida and Dr. Peter Elias have overcome a challenge that may lead to important advances in the treatment of rosacea.

In earlier studies, they found that stress to the skin cells caused by ultraviolet radiation, heat or other rosacea triggers results in a cascade of events in the body in which the production of one substance leads to another. These substances include the protective antimicrobial peptide called cathelicidin (CAMP) that speeds physical repair, but worsens rosacea symptoms. The next step was to discover how to reduce this peptide without limiting the body’s ability to defend and repair itself.

In order to preserve CAMP’s benefits, the researchers examined elements along the pathway to its production and found a substance known as SP1 (a type of lipid) that is responsible for the upstream signal that eventually leads to increased CAMP production.

Fortunately, they discovered there is another lipid metabolite, known as C1P, that stimulates production of other protective peptides, which in turn suppress the overproduction of CAMP, the substance that leads to rosacea symptoms. They noted that blocking or changing the metabolic pathway with a medication at this particular point could suppress inflammation and simultaneously stimulate the skin’s antimicrobial defense, potentially leading to the development of new types of therapy for rosacea.

Publication of results: Jeong SK, Kim YI, Shin KO, et al. Sphingosine kinase 1 activation enhances epidermal innate immunity through sphingosine-1-phosphate stimulation of cathelicidin production. Journal of Dermatological Sciences. 2015 June 19 pii: S0923-1811(15)30010-4.

The role of mast cells in rosacea inflammation Dr. Anna Di Nardo, associate professor of medicine at the University of California-San Diego.

A team led by Dr. Anna DiNardo, associate professor of medicine of the University of California-San Diego, found that mast cells play a direct role in the activation of certain types of cathelicidins, an enzyme involved in the innate immune response that is over-produced in people with rosacea. Studying the process in mice, Dr. DiNardo's team determined that when exposed to a neuropeptide called PACAP, mast cells produce enzymes that trigger the production of cathelicidins. In mice bred to lack mast cells, this chain reaction did not occur.

In their next study, also supported by an NRS research grant, Dr. DiNardo's team will determine whether use of a mast cell stabilizer known as cromolyn sodium will decrease symptoms of rosacea. In addition, they will test to see if levels of the enzymes tryptase and chromotryptase -- typically higher in rosacea patients -- revert to normal after application of the mast cell stabilizer, and which of the enzymes is more important in the process.

Publication of results: Mascarenhas NL, Wang Z, Chang YL, Di Nardo A. TRPV4 mediates mast cell activation in cathelicidin-induced rosacea inflammation. J Invest Dermatol 2017 Apr;137(4):972-975. doi: 10.1016/j.jid.2016.10.046. Epub 2016 Nov 28.

Factors that affect rosacea: A cohort-based study on twins Dr. Meg Gerstenblith and Dr. Daniel Popkin, assistant professors of dermatology, Case Western Reserve University

Genetics have long been thought to play a role in rosacea, but researchers had yet to isolate their influence. In what may be the first study of rosacea to measure and define genetic and environmental contributions, Dr. Daniel Popkin, assistant professor of dermatology at Case Western Reserve University, and colleagues have found that genetics and environmental factors may contribute equally to the disorder.

To examine and isolate the potential genetic and environmental factors that may be involved in rosacea, the researchers studied a sample of 275 twin pairs (550 individuals) in whom at least one sibling has rosacea, recruited at the Twin Day Festival in Twinsburg, Ohio, near Cleveland. The study group included 233 pairs of identical twins and 42 pairs of nonidentical twins. Participants were scored based on the National Rosacea Society’s grading system and a physical examination by board-certified dermatologists. The researchers found that the disorder occurred significantly more often in both identical twins than in both members of a pair of fraternal (nonidentical) twins, and noted the association held true even after such common rosacea risk factors as age and skin type were accounted for, suggesting that genetics may play a substantial role in rosacea.

The researchers then evaluated factors such as gender, age, smoking/alcohol consumption history, heart health and lifetime sun exposure to determine the influence of certain environmental variables on the disease, and found that a higher rosacea score was positively associated with age and lifetime ultraviolet radiation exposure. They also found correlations with body mass index (BMI), smoking, alcohol consumption, cardiovascular issues and skin cancer. The researchers noted that although alcohol has been found to be a trigger of rosacea symptoms, it has not been identified as risk factor for development of the disorder. However, they did point out that the correlation between BMI (body mass index) and cardiovascular disease may be an opportunity for additional analysis. Recent studies have further highlighted a potential link between rosacea and the increased risk of cardiovascular disease.

Publication of results: Aldrich N, Gerstenblith M, Popkin D, et al. Genetic vs Environmental Factors That Correlate With Rosacea: A Cohort-Based Survey of Twins. JAMA Dermatology . 2015;151(11):1213-9.

Norepinephrine and adenosine-5’-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells Dr. Richard Granstein, chairman of dermatology at Cornell University

Dr. Granstien and a team of researchers at the Weill Cornell Medical College studied the synergistic relationship between norepinephrine (NE) and adenosine-5’-triphosphate (ATP) and its effect on endothelial cells under conditions of stress. They found that under conditions of stress, the sympathetic nerves become activated and release both NE and ATP in the presence of dermal blood vessels. The complex interactions of NE and ATP induce an over-secretion of the cytokine IL-6, which plays a role in the differentiation of Th17 helper cells. Th17 cells are autoimmune cells that are implicated in inflammatory skin diseases such as psoriasis and rosacea.

Studies such as this help to explain how our nervous system and immune system interact and how it may impact our skin. The results of this study may indicate how stress can exacerbate skin inflammation. Dr. Granstein and his team wrote that more research is needed to better understand these complex interactions and draw any conclusions.

Publication results: Stohl LL, Zang JB, Ding W, Manni M, Zhou XK, Granstein RD. Norepinephrine and adenosine-5’-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells. Cytokine 2013;53:605-612.

Kallikrein protease inhibitors in the pathogenesis of rosacea Dr. Ulf Meyer-Hoffert and Dr. Thomas Schwartz of the Department of Dermatology, University Clinic Schleswig-Holstein, Germany.

Kallikrein-related peptidases (KLKs), a family of proteases recently identified as having a possible role in the development of rosacea, may help provide a pathway to controlling rosacea’s signs and symptoms, according to an article by Drs. Jan Fischer and Ulf Meyer-Hoffert of the University Hospital Schleswig-Holstein in Germany in the journal Thrombosis and Haemostasis .

Proteases are enzymes that occur in all lifeforms, from single-celled organisms to plants and animals, for various metabolic processes. For example, acid proteases secreted into the stomach enable the digestion of protein in food, and other proteases present in blood play a role in clotting.

Kallikrein-related peptidases have many biochemical activities. Already recognized as biomarkers for cancer, certain types of KLKs in the surface of the body have been found to be involved in the normal shedding of the outermost layer of skin, the authors noted. Moreover, KLKs have been described as processing cathelicidins, protective antimicrobial peptides that can speed physical repair, but have been found to worsen rosacea symptoms.

The authors noted that interference in KLK activity may have therapeutic potential. For example, an antibiotic with anti-inflammatory properties was shown to inhibit KLKs and the subsequent activation of cathelicidin, which may be why it is effective in rosacea, they said.

They noted that further study of regulation of KLK activity may yield insights into therapeutic intervention.

Publication of results: Fischer J, Meyer-Hoffert U. Regulation of kallikrein-related peptidases in the skin – from physiology to diseases to therapeutic options. Thrombosis and Haemostasis 2013;110:442-449.

Functional role of PACAP and its receptors in neurovascular aspects of rosacea Dr. Ferda Cevikbas, postdoctoral fellow, and Dr. Martin Steinhoff, professor of dermatology, University of California-San Francisco.

Researchers have found a potential connection between the nervous system and the redness and stinging of subtype 1 (erythematotelangiectatic) rosacea.

Drs. Ferda Cevikbas and Martin Steinhoff, University of California-San Francisco, noted that the flushed face of rosacea is often accompanied by stinging and burning, signs of nerve activation. They theorized this may signal a dysfunction in communication between the nerves and the vascular system.

A neuropeptide — a molecule linked to the nervous system — called pituitary adenylate cyclase-activating polypeptide (PACAP) was recently recognized as playing a role in regulating the blood vessels, they noted. However, while PACAP has been identified as affecting inflammation in various animal diseases, its role in human skin and skin disease is poorly understood.

Drs. Cevikbas and Steinhoff administered PACAP into skin on the underside of the forearms of volunteers, and found that the neuropeptide caused flushing, swelling and itching, though not pain. The investigators noted that PACAP may have a role in pain in combination with other factors, and suggested that blocking PACAP may be a potential treatment to relieve the redness and flushing of rosacea.

Cellular and molecular analysis of transient receptor potential (TRP) ion channels and neurovascular regulation in rosacea patients Dr. Jamison Feramisco, molecular medicine fellow in dermatology, and Dr. Martin Steinhoff, professor of dermatology, University of California-San Francisco.

A malfunction in part of the body's nervous system may be linked to the redness as well as the bumps and pimples of rosacea, according to a recently completed study by Dr. Akihiko Ikoma and colleagues at the University of California-San Francisco.

The investigators took blood and biopsy samples from members of 10 families in which some individuals had rosacea. Through innovative biochemical and genetic testing, they found those with rosacea suffered from irregularities in a variety of transient receptor potential (TRP) ion channels, which serve as prominent components of the nervous system.

Because a variety of TRP channels can be activated by factors that trigger rosacea symptoms, the researchers noted, impaired functioning of these channels may play a critical role in the development of the disorder.

For example, TRPV1 is activated by capsaicin, a substance present in spicy food, as well as by heat or under inflammatory conditions. TRPV2 may play a role in innate immunity, inflammation and the sensing of heat. TRPV4 is also activated by moderate heat and may promote flushing, stinging and burning.

The researchers also found the immune system of those with subtype 1 (erythematotelangiectatic) rosacea, characterized by flushing and redness, showed significantly increased reactivity for TRPV2 and 3, as well as gene expression of TRPV1. Subtype 2 (papulopustular) rosacea, characterized by bumps and pimples, showed enhanced reactivity of the immune system for TRPV2 and 4, and had gene expression of TRPV2. These TRP nerve channels may therefore be promising targets in the development of future rosacea therapy, the researchers said.

Publication of results: Sulk M, Seeliger S, Aubert J, et al. Distribution and expression of non-neural transient receptor potential (TRPV) ion channels in rosacea. Journal of Investigative Dermatololgy 2012;132:1253-1262.

Role of skin sympathetic nerve activity in rosacea Dr. Thad Wilson, associate professor of physiology and medicine; Dr. Kumika Toma, postdoctoral fellow; Dr. Michael Tomc, associate professor of otorhinolaryngology; and Dr. Dawn Sammons, assistant professor of dermatology, Ohio University.

New medical research into the process of facial flushing and redness has found that individuals with rosacea produce greater nerve, blood flow and sweating responses than people without the disorder when exposed to increased heat or stress. Results of the National Rosacea Society-funded study also uncovered a role for the sympathetic nervous system, which controls the “fight or flight” response and other key involuntary functions such as heart rate, digestion, breathing and perspiration.

To increase body temperature, the researchers had 10 rosacea patients and 10 healthy control individuals wear a tight-fitting suit lined with tubes carrying water heated to 115°F until their body temperature increased by approximately 2°F. Each person was then precisely measured for supraorbital nerve activity (a nerve just above the eyebrow that serves the forehead skin), forehead skin blood flow and forehead sweat rate.

The researchers found that rosacea patients had higher skin blood flow and sweating rates compared to normal subjects both before and after the heating began, and their skin blood flow and sweating also began to increase more rapidly during heating.

In a separate part of the study, heart rate, supraobital nerve activity and blood pressure were monitored in 12 rosacea patients and 12 healthy control subjects during mental and physical tasks. These included performing fast-paced mental subtraction exercises for two minutes, using hand gestures to indicate answers, and tightly squeezing a handgrip for two minutes.

While heart rate and blood pressure were the same between the groups during the hand exercises, skin blood flow was higher duringmental arithmetic in the rosacea patients. The rosacea patients also experienced heightened sympathetic nerve activity compared to those without rosacea during both the mental and physical portions of the test. The greater responses in rosacea patients occurred in the sympathetic nervous system, a part of the body’s autonomic nervous system that controls involuntary functions such asheart rate, digestion, breathing and perspiration. This portion of the autonomic nervous system functions largely below the level of consciousness and has been shown to respond to emotion.

Clinical and molecular analysis of differences between rosacea and photoaging Dr. Yolanda Helfrich, assistant professor of dermatology at the University of Michigan.

In a study of 27 patients with subtype 1 rosacea, 18 with subtype 2 rosacea, 19 with photodamaged skin and prominent telangiectasia and 11 control subjects without rosacea or sun damage, Dr. Yolanda Helfrich, assistant professor at the University of Michigan, found that patients with subtype 1 rosacea had a greater number of mast cells that were discharging their contents than the control subjects.

Mast cells are found in skin tissue surrounding blood vessels and nerves, and release many mediators involved in rosacea, including histamine, associated with flushing. Since virtually all the mast cells in the rosacea patients were positive for interleukin 17, Dr. Helfrich noted that this cytokine — which plays a key role in development of rheumatoid arthritis and psoriasis — may also contribute to rosacea.

In addition, though some individuals with skin aging due to sun exposure also had prominent facial telangiectasia, she found significant biological differences between this group and those with rosacea, suggesting that the presence of visible blood vessels alone should not necessarily lead to a diagnosis of rosacea.

Role of beta-arrestin in cutaneous flushing Dr. Robert W. Walters, assistant professor, Division of Dermatology, and Dr. Robert J. Lefkowitz, professor, Department of Medicine, Duke University Medical Center.

Researchers have now identified the molecular pathway for flushing caused by niacin — also known as vitamin B3 or nicotinic acid, and found in many foods — according to a study recently completed by Dr. Robert Walters and colleagues at Duke University and funded by the National Rosacea Society. The new findings may lead to future improvements in the treatment or prevention of rosacea, which is commonly associated with flushing.

"So little is known about the flushing responses in rosacea, and the first step toward their control is to understand the nature of their causes," Dr. Walters said. "Since niacin is often a trigger factor for flushing, it was important to investigate this response at the molecular level."

He noted that this substance is an essential vitamin found in an extensive range of foods, including foods reported to trigger rosacea flare-ups in some individuals, such as beef liver, yeast, avocadoes and spinach. While niacin deficiency leads to pellagra — a disease associated with skin problems, weakness and dementia — he noted that it has also been associated with severe flushing in individuals taking large amounts as a supplement.

The researchers studied this process in microscopic cultures of cells and found that when one of the body's niacin receptors — cell surface protein GPR109A — is stimulated, both G-proteins and beta-arrestin proteins are activated. A receptor is a cellular structure that accepts the molecular structure of a specific chemical agent, and then acts on nervous tissue to produce a physiological response.

In the new study, the investigators found that niacin-like drugs stimulating only G-proteins do not induce flushing, suggesting that it is instead the beta-arrestins that cause the flushing. The beta-arrestins were further implicated when it was observed that they are required for activation of the enzyme cPLA2, which produces molecules that act directly on blood vessels in the skin to increase blood flow. As final proof, beta-arrestin activated by niacin was demonstrated to be a requirement for the flushing to occur.

"By defining the molecular pathway for flushing that begins with niacin, new therapies might be developed to block this process," Dr. Walters said. He noted that other causes of flushing may utilize the same pathway, suggesting it could also be an important mechanism for flushing in general.

Rosacea prevalence and relationship to cutaneous photodamage Dr. Patricia Fitzpatrick, Department of Public Health Medicine & Epidemiology, University College, Dublin, Ireland and Dr. Frank Powell, Consultant Dermatologist, Mater Misericordiae Hospital, Dublin, Ireland.

A study funded by the National Rosacea Society provides further evidence that rosacea may be far more common than widely believed, and also assesses the potential significance of sun exposure.

The study, presented at the 2008 British Association of Dermatologists meeting by Dr. Maeve McAleer and colleagues at Mater Misericordiae University Hospital and the School of Public Health and Population Science, University College, Dublin, found that 14.4 percent of 1,000 subjects examined in Ireland had rosacea.

This high prevalence rate is comparable to preliminary study results that found rosacea in 16 percent of Caucasian women in the United States. The U.S. data, reported by Dr. Alexa Boer Kimball, director of the clinical unit for research in skin care at Harvard Medical School, were based on examination of high-resolution digital photographs of 2,933 volunteers. Another study of 806 office workers examined in Sweden found a rosacea prevalence of 14 percent in women and 6 percent in men.

While the more recent studies are based on the standard classification system published by the National Rosacea Society Expert Committee for the Classification and Staging of Rosacea in 2002, Dr. McAleer noted that earlier studies did not have defined criteria for diagnosing the condition. To investigate the potential effects of sun exposure, the Irish study included 500 residents of the Aran Islands, an area off the western coast of Ireland, and 500 hospital workers in Dublin. The Aran Islanders reportedly had greater sun exposure, due to their outdoor occupations of fishing and farming, compared with the hospital workers.

The researchers found that the Aran Islanders and the hospital workers had similar rates of subtype 2 (papulopustular) rosacea, characterized by bumps and pimples, at 2.8 percent and 2.6 percent, respectively. However, they found that 16.3 percent of the Aran Island group had subtype 1 (erythematotelangiectatic) rosacea, characterized by facial redness, compared with a subtype 1 prevalence rate of 6.8 percent in the hospital workers (a statistically significant difference).

Role of proteases and endothelin-converting enzyme in rosacea Dr. Martin Steinhoff, department of dermatology, University of Muenster, Germany.

Dr. Martin Steinhoff and Dr. Thomas Luger, Department of Dermatology, University of Muenster, have been studying biological receptors, structures in human cells that bind with particular substances in the body to cause certain reactions or responses. Receptor dysfunctions may lead to disease, including rosacea, and thus identification of the mechanisms of these processes often leads to important therapeutic advances.

For example, proteinase-activated receptor 2 (PAR 2) can serve as a receptor for several molecules, including dust mite antigens and bacterial proteases, which have a high impact on inflammatory response in the skin. In a National Rosacea Society-funded study, the researchers are now defining which of the type of proteases known as kallikreins may be involved in the inflammatory responses as well as the stinging, burning and itching of rosacea. As part of their multi-pronged investigation, they recently discovered that endothelin-converting enzyme (ECE) acts on the neuropeptides known as substance P and calcitonin gene-related peptide (CGRP), and noted that any substance that inhibits ECE may be effective in the treatment of rosacea.

Structural and biological changes in rosacea skin induced by the 595nm long-pulse dye laser and intense pulsed light. Dr. Payam Tristani-Firouzi, assistant professor, and Dr. Nancy Samolitis, visiting professor, department of dermatology, University of Utah.<

New clues to help unlock the mystery of rosacea were identified in a National Roscacea Society-funded study in which researchers used advanced technology to evaluate the skin of patients successfully treated with pulsed dye lasers (PDL) or intense pulsed light (IPL).

"We are pleased to see interesting findings in this small pilot study that not only help reveal the underlying disease process, but may also provide a basis for developing more targeted therapy in the future," said Dr. Nancy Samolitis, visiting instructor in dermatology at the University of Utah and investigator in the study.

Before treatment the researchers found elevated levels of vascular endothelial growth factor (VEGF), associated with the development of visible blood vessels (telangiectasia), in five of the 10 rosacea patients. In four of these subjects — three in the PDL group and one in the IPL group — the level decreased after therapy.

Eight of the patients were also found to have elevated cathelicidins, natural antimicrobial agents linked in previous research to rosacea inflammation, and the level was reduced in three IPL- and two PDL-treated patients after treatment.

"The results of this study suggest that PDL and IPL may have a role in the reduction of telangiectasia," Dr. Samolitis said. "Our findings particularly suggest that cathelicidins and VEGF may play a role in the pathogenesis of rosacea and warrant further study."

Both the physicians and patients rated significant improvement in rosacea severity in the 10 individuals treated.

Although light sources are commonly used to remove visible blood vessels, their usefulness in reducing the redness of rosacea requires further study. Drug therapy is usually prescribed to control the bumps and pimples of rosacea and has been shown to significantly reduce the incidence of flare-ups.

Mite-related bacteria may induce rosacea inflammation Dr. Kevin Kavanagh, Department of biology, National University of Ireland, Maynooth, and Dr. Frank Powell, Consultant Dermatologist, Mater Misericordiae Hospital, Dublin.

Although they are normal inhabitants of human skin and cannot be seen, microscopic mites known as Demodex folliculorum may actually be something to blush about, as a new study funded by the National Rosacea Society (NRS) demonstrated for the first time that these invisible organisms may be a cause or exacerbating factor in rosacea.

"While it is well established that Demodex occur in far greater numbers on the faces of people with rosacea, it was uncertain whether they play a role in the development of the disorder," said Dr. Frank Powell, consultant dermatologist at Mater Misericordiae Hospital in Dublin, Ireland, who conducted the study along with colleagues at the National University of Ireland-Maynooth. "In other words, which came first, the mites or the rosacea? And now there is evidence that it might be the mites."

In the new study, published in the British Journal of Dermatology , the researchers identified Bacillus oleronius as distinct bacteria associated with Demodex mites. When analyzing blood samples using a peripheral blood mononuclear cell proliferation assay, they discovered that B. oleronius stimulated an immune system response in 79 percent of 22 patients with subtype 2 (papulopustular) rosacea, compared with only 29 percent of 17 subjects without the disorder.

"The immune response results in inflammation, as evident in the papules (bumps) and pustules (pimples) of subtype 2 rosacea," Dr. Powell said. "This suggests that these bacteria found in the mites could be responsible for the inflammation associated with the condition."

Dr. Powell noted that the potential role for the bacteria in subtype 2 rosacea is also supported by the fact that effective treatment includes antibiotics that destroy B. oleronius . Interestingly, he said, antibiotics that are not harmful to these bacteria generally are not effective in the management of rosacea.

"Although the mechanism of antibiotics in treating rosacea is not definitively understood, it has long been suggested that they work through anti-inflammatory action," he said. "However, other anti-inflammatory drugs are ineffective in treating rosacea, and immunosuppressive agents such as steroids can ultimately make the inflammation worse."

The researchers concluded that their study shows consideration must also be given to the potential for antibiotics to affect microorganisms such as B. oleronius or other follicular or mite-related bacteria.

Publication of results: Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. British Journal of Dermatology 2007;157:474-481 .

Cell biologic effects of ATP on endothelial cells Dr. Richard Granstein, chairman, Department of Dermatology, Cornell University.

Researchers have found that one of the most common and hard-working substances in the body may have a Jekyll and Hyde quality in rosacea patients, assuming a darker role when activated by flare-up triggers.

"Sometimes too much of a good thing turns out to be bad," noted Dr. Richard Granstein, chairman of dermatology at Cornell University, lead investigator in the ongoing research funded by the National Rosacea Society (NRS). "The key to improving therapy is to identify those inflammatory pathways involved with rosacea so they can be better controlled."

The researchers have discovered that when adenosine 5'-triphosphate (ATP) — a neurotransmitter and carrier of chemical energy throughout the body — is released into the skin by the nerves, a cascade of microscopic events may occur in rosacea patients that ultimately leads to the bumps and pimples of subtype 2 (papulopustular) rosacea.

"As with many disorders, inflammation represents a normal body process gone awry," Dr, Granstein explained. Inflammation is a protective response to injury or destruction of tissues that serves to destroy, dilute or wall off both the agent of injury and the injured tissue, so that tissue can repair itself.

The most evident outward signs and symptoms of inflammation are pain, heat, redness, swelling and loss of function. However, the biochemical processes that accomplish this reaction are complex, and involve dilation of blood vessels accompanied by increased blood flow, release of fluids and the movement of leukocytes — blood cells that engulf and digest bacteria and fungi and are an important part of the body's defense system, according to Dr. Granstein.

While ATP has many functions in the body, its role in the development of rosacea may involve its job as a messenger from the nerves. The nervous system regulates blood flow to the skin, using ATP to prompt the dilation of blood vessels following exposure to rosacea triggers such as sunlight, emotional stress or alcohol. This process may result in the flushing and redness of subtype 1 (erythematotelangectatic) rosacea.

According to Dr. Granstein, ATP has also been shown to be involved in the movement and buildup of leukocytes onto endothelial cells — cells that line the blood vessels. In rosacea, the researchers found that endothelial cells respond to ATP with changes in the expression of inflammatory cytokines and other substances that act to recruit inflammatory cells and may lead to rosacea's bumps and pimples.

"As we continue to learn more about the biochemical processes that lead to rosacea, we should increasingly be able to identify how signs and symptoms occur in order to develop appropriate means to prevent them," Dr. Granstein said. He noted that, while current therapies may block some of these pathways, the process is still unclear and should become increasingly evident through continuing research.

In previous NRS-funded studies, Dr. Granstein's team demonstrated that ultraviolet B (UVB) radiation, which is found in sunlight and causes sunburn, may increase vascular endothelial growth factor (VEGF), a regulator of blood vessel growth that may cause visible blood vessels (telangiectasia) associated with subtype 1 rosacea. In addition, they found that UVB may increase interleukin 8, which plays a role in inflammation.

Publication of results: Seiffert K, Ding W, Wagner JA, Granstein RD. ATPγS enhances the production of inflammatory mediators by a human dermal endothelial cell line via purinergic receptor signaling. Journal of Investigative Dermatology 2006;126:1017-1027

Allergy-like reaction may trigger inflammation in rosacea Dr. Richard L. Gallo, associate professor of dermatology and pediatrics at the University of California - San Diego, and Dr. Kenshi Yamasaki, Veterans Medical Research Center

The bumps (papules) and pimples (pustules) of rosacea, a widespread facial disorder affecting an estimated 14 million Americans, may be the result of an allergy-like reaction to environmental and emotional triggers, according to new study results presented at the National Rosacea Society (NRS) research workshop during the annual meeting of the Society for Investigative Dermatology in Philadelphia. The seventh annual NRS workshop was attended by more than 130 medical scientists from around the world.

"We are very excited about these findings because they may provide the basis for improving the treatment and management of this condition," said Dr. Richard Gallo, chief of the division of dermatology at the University of California-San Diego and lead investigator of the NRS-funded study. "By defining the process leading to the inflammation, new medications might be developed to block these effects."

Dr. Gallo explained that when the normal immune system is faced with any of a broad range of potential dangers — such as sun exposure, emotional stress, heat and spicy foods, among many others — receptors recognize potential danger and protect the body by prompting the production of protective substances that isolate and neutralize any harmful effects. With rosacea, however, these protective substances, like overzealous guards, turn the body on itself, leading to inflammation.

Using advanced mass spectrometry technology to analyze the biochemical composition of proteins in rosacea patients, the researchers discovered an abnormality in the production of protective molecules known as cathelicidins, Dr. Gallo said. In normal patients, the cathelicidins are found in a form that is inactive and would not lead to bumps and pimples. In rosacea patients, the forms of cathelicidins are different and lead to skin inflammation. The cause of this abnormality in cathelicidins seems to be due to an equally important problem in rosacea — an overabundance of yet another substance, called kallikrein, which can spur dormant cathelicidins into action.

"It appears that the combination of these two substances at abnormally high levels is a double whammy for rosacea patients," Dr. Gallo noted.

The researchers recently completed the picture when they were able to demonstrate that this process is linked to the actual formation of rosacea signs and symptoms. The skin of mice injected with the cathelicidins found in rosacea patients showed a dramatic inflammatory response — including bumps and pimples — while mice injected with normal cathelicidins showed no inflammation, either visually or under a microscope.

"The next step is to test these findings in human subjects through various therapeutic interventions," Dr. Gallo said. "As we gain a thorough understanding in humans, we can look for new medications that block this process in order to treat or prevent the inflammation associated with rosacea."

Publication of results: Yamasaki K, DiNardo A, Bardan A, et al. Increased serine protease activity and cathelicidins promotes skin inflammation in rosacea. Nature Medicine 2007;13:975-980.

Role of serine proteinases and proteinase-activated receptors (PAR-2 and PAR-4) in the pathophysiology of rosacea. Dr. Martin Steinhoff and Dr. Thomas Luger, Department of Dermatology, University of Muenster.

New research funded by the National Rosacea Society has found that certain molecular receptors and their activators may play a significant role in producing the redness, visible blood vessels and inflammation of rosacea.

A receptor is a structure in human cells that binds with particular activating substances in the body to trigger certain reactions or responses. Dysfunction of receptors often leads to disease. Accordingly, identification of the mechanisms of these processes, which may then be adjusted, often leads to important therapeutic advances.

Dr. Steinhoff and Dr. Luger examined how proteinase-activated receptor 2 (PAR-2) and its agonists may affect endothelial cell function in rosacea skin. PAR-2 can serve as a receptor for several molecules, including dust mite antigens and bacterial proteases, which have a high impact on inflammatory response in the skin.

The researchers found that PAR-2 agonists induce upregulation of several molecules related to microvascular endothelial cells, and that they regulate proliferation and differentiation in keratinocytes and induce the release of cytokines.

Additionally, PAR-2 agonists were found to cause erythema and vasodilation in human skin in in vivo studies, indicating a functional role for PAR-2 in human cutaneous blood vessel formation. Dr. Steinhoff and Dr. Luger also demonstrated that PAR-2 plays an important role in leukocyte adhesion to endothelial cells in the skin of mice. Moreover, in studying the effects of PAR-2 agonists on keratinocyte function, it was found that PAR-2 activates NFkB in humans, indicating a potential important role of this receptor in skin inflammation.

The researchers are now conducting further studies to determine whether PAR-2 or its agonists affect the expression of VEGF, known to trigger the formation of visible blood vessels, or nitrous oxide, which may hypothetically play a role in rosacea.

Glycomics analyses of tear fluid for the diagnostic detection of ocular rosacea. Dr. Mark J. Mannis, Department of Ophthalmology, University of California - Davis.

In a study funded by a grant from the National Rosacea Society (NRS), researchers may have uncovered clues that may lead to a diagnostic marker for subtype 4 (ocular) rosacea, a chronic condition that may have severe consequences if left untreated — including reduced vision. In publishing the final study results in the medical Journal of Proteome Research , 1 the researchers noted that ocular rosacea often may be difficult to diagnose, especially in the absence of signs of rosacea on the skin. In addition, it may be frequently overlooked by non-eye doctors.

"Ocular rosacea is potentially a vision-threatening condition that may be easily missed," said Dr. Mark Mannis, chairman of ophthalmology at the University of California, Davis and one of the study's investigators. "We are excited that our study may ultimately lead to the first diagnostic test that could alert physicians to eye involvement before it grows more serious."

Samples of tears from 16 ocular rosacea patients and 21 individuals without rosacea were collected by Dr. Mannis and colleagues and were analyzed for the presence of oligosaccharides, a type of carbohydrate that may be found in the mucus component of the tear fluid. Oligosaccharides are known to be sensitive to the biochemical environment and could be an indicator of disease states.

The researchers found that the presence of high levels of oligosaccharides may be a diagnostic indication of ocular rosacea and that high levels of 13 particular types of the compound were associated with rosacea and may serve as more specific markers for the disorder. Since a general increase of oligosaccharides may not necessarily be specific to rosacea, they emphasized that the types of oligosaccharides found in greatest abundance in rosacea patients should be evaluated in further research for their specificity as markers for ocular rosacea.

Ocular rosacea may be present in varying degrees in up to 50 percent of rosacea sufferers. In an NRS survey of 1,780 rosacea patients reporting ocular symptoms, only 27 percent said they had been diagnosed with the condition, possibly indicating underdiagnosis. Typical symptoms of ocular rosacea may include a watery or bloodshot appearance, foreign body sensation, burning or stinging, itching, light sensitivity, blurred vision, and visible blood vessels or redness of the eyelid. A history of styes and feeling of dryness in the eyes are also key indicators.

"We plan to further investigate which types of oligosaccharides are the best indicators of rosacea in order to achieve even greater accuracy in distinguishing ocular rosacea from normal patients," Dr. Mannis said.

Publication of results: An HJ, Ninonuevo M, Aguilan J, Liu H, Lebrilla CB, Alvarenga LS, Mannis MJ. Glycomics analyses of tear fluid for the diagnostic detection of ocular rosacea. Journal of Proteomic Research 2005 Nov-Dec;4(6):1981-7.

Effects of neuropeptides and sebocyte-derived factors on human dermal microvascular endothelial cells in the skin: A possible mechanism for the development of vascular and inflammatory lesions in rosacea. Dr. Richard Granstein, Cornell University Medical School.

Results from previous research funded by the National Rosacea Society have led investigators Dr. Richard Granstein and colleagues at the Cornell University Medical School to focus in their current study on adenosine triphosphate (ATP), a natural substance in the body that may play a key role in the flushing, telangiectasia and bumps and pimples of rosacea.

In their earlier NRS-funded research investigating the biochemical pathways that regulate the growth of new blood vessels, flushing and inflammation, Dr. Granstein's group demonstrated that ultraviolet B (UVB) radiation, found in sunlight, may increase vascular endothelial growth factor (VEGF), a regulator of blood vessel growth, and may also increase interleukin 8, which plays a role in inflammation.

In addition, the researchers' early data indicated that endothelial cells — cells that line the blood vessels — respond to ATP with changes in the expression of inflammatory cytokines, which are proteins that act to recruit inflammatory cells. ATP also may affect vascular tone by inducing vasodilation — enlargment of the blood vessels — which may result in the appearance of redness.

Known as the "molecular currency" of intracellular energy transfer, ATP acts like a rechargeable battery and is able to store and transport chemical energy within cells. The substance not only is present in neurons, or nerve cells, which are affected by rosacea triggers such as stress, but is also essential to many cellular functions, according to Dr. Granstein.

"Its widespread presence suggests there may be many pathways by which ATP may mediate rosacea," Dr. Granstein said. "ATP may play a significant role in response to inflammation, and have a profound effect in response to rosacea triggers. If so, blocking these pathways may lead to major advances in therapy."

The researchers plan to look at this substance under a variety of different conditions and in different concentrations to track its potential role in rosacea.

Experimental studies in the pathogenesis of rosacea. Dr. YaXian Zhen, scientific researcher, and Dr. Albert Kligman, professor of dermatology, University of Pennsylvania.

Dr. Zhen and Dr. Kligman explored similarities between acne vulgaris and rosacea. The researchers noted that in studies of more than 100 women with rosacea, about 40 percent reported having adolescent acne. Moreover, about 30 percent to 40 percent of the women who experienced acne during adolescence exhibited moderate flushing responses to common rosacea triggers.

In a further investigation of 15 female rosacea patients and five women without rosacea as controls, the researchers found that the rosacea patients had more characteristics common to acne than the control subjects. Facial oil production was about 40 percent greater; microcomedones, precursor to visible comedones (blackheads), were twice as numerous and larger in the rosacea patients than in the controls; and the density of the acne bacterium, Propionibacterium acnes , was nearly twice that of controls.

A bioengineering evaluation of facial rosacea. Dr. Diane Thiboutot, professor of dermatology; Hilma Benjamin and Dr. Klaus Helm, Division of Dermatology, Pennsylvania State University College of Medicine.

In a study of the moisture level, elasticity, skin thickness, extent of photodamage and other characteristics of rosacea skin, investigators found rosacea patients had thicker facial skin than normal subjects, which might be a result of edema (swelling). However, the researchers found no significant difference in skin water loss and elasticity between the 20 rosacea patients and 20 patients without rosacea.

Their questionnaire revealed that rosacea patients, who are often affected by sun exposure, were more likely to keep the upper body covered from the sun while doing outdoor work and were less likely to have had sunburns that required medical attention. Despite their apparently reduced sun exposure, however, those with rosacea had more visible blood vessels and blood vessels with a larger diameter.

Vascular endothelial growth factor (VEGF), a regulator of blood vessel growth that may be associated with sun exposure, was highly expressed in the sebaceous glands of the rosacea patients, Dr. Thiboutot said. She noted that previous research has found VEGF may be involved in the formation of visible blood vessels in rosacea, and that rosacea patients may therefore be especially sensitive to sunlight.

Perceptions of self in persons with rosacea. Karol Burkhart Lindow, RN, C, CNS, assistant professor of nursing; Deb Shelestak, RN, MSN; Joan Lappin, RN, MSN, Kent State University.

In a small pilot study funded by a grant from the National Rosacea Society, 27 rosacea patients and a control group of 17 people without rosacea completed a survey about rosacea and the Tennessee Self-Concept Scale (TSCS), once at the beginning of the study and again after three months. No statistically significant differences in self-concept or role performance were shown between the gross scores of the rosacea group and the control group.

"There does, however, appear to be a logical pattern to the test scores, based on severity of condition," Lindow said. "For example, an interesting trend is seen of decreasing [self-image] scores corresponding with an increasing severity of illness."

The investigators believed the small sample size may explain the lack of statistically significant findings. Changes in self-concept would be expected to be subtle, correlating with the relative severity of the disorder, and therefore would be more easily detected in a larger sample size. They recommended a larger study be undertaken to examine this issue.

Publication of results: Lindow KB, Shelestak D, Lappin J. Perceptions of self in persons with rosacea. Dermatology Nursing 2005;17(4):249-254,314.

The role of bacterial antigen(s) in the etiology and persistence of papulopustular bacteria. Dr. Kevin Kavanagh, Department of Biology, National University of Ireland - Maynooth, and Dr. Frank Powell, consultant dermatologist, Mater Misericordiae Hospital, Dublin.

Bacteria associated with microscopic mites known as Demodex folliculorum may play a role in the development of papulopustular (subtype 2) rosacea, according to the results of a study funded by a National Rosacea Society grant and reported at the 2004 annual meeting of the Society for Investigative Dermatology.

In the completed study, Dr. Kevin Kavanagh and colleagues found that the bacterium Bacillus oleronius stimulated an immune system response, inducing high levels of T-cell proliferation, in 79 percent of patients with subtype 2 rosacea, compared with only 29 percent of patients without the disorder. T-cell proliferation induces an inflammatory response, evident as papules and pustules.

"This indicates that the Bacillus bacteria found in the Demodex mite produce an antigen that could be responsible for the tissue inflammation associated with papulopustular rosacea," Dr. Kavanagh said.

The researchers located the bacteria in Demodex folliculorum , which are normal inhabitants of human skin. Because these microorganisms often occur in much greater numbers in patients with rosacea, researchers have long theorized that they may play a part in the development of the disorder.

The researchers offered several possibilities that may explain how Demodex and bacteria interact to cause inflammation in rosacea. The Demodex mites may carry the pathogenic bacteria into areas of the face susceptible to the changes of rosacea, so that the increased mite density in rosacea patients may result in a higher density of bacteria that produce the papules and pustules. Alternatively, Demodex mites may be attracted to an area of facial skin rich in these bacteria and increase in numbers in this "fertile territory."

Another possibility is that the mites in rosacea patients are infected with these bacteria, which in turn produce stimulatory antigens that trigger the disorder in susceptible patients.

Dr. Kavanagh noted that the potential role for bacteria in causing papulopustular rosacea is supported by the fact that typical treatment for rosacea initially includes oral antibiotics that destroy B. oleronius . Interestingly, he said, antibiotics that are not harmful to these bacteria generally are not effective in the management of rosacea.

Moreover, the possibility that antigens may play a role in disease processes has been demonstrated in other disorders. For example, antigens produced by Streptococcus and Staphylococcus bacteria have been linked with such disorders as psoriasis, food poisoning and toxic shock syndrome.

Dr. Kavanagh and his colleagues are now developing antibodies against the antigen produced by B. oleronius to confirm its presence on the faces of patients with papulopustular rosacea and to define its relationship with Demodex mites.

Publication of results: Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. British Journal of Dermatology 2007;157:474-481.

Immune system may trigger onset of rosacea symptoms Dr. Richard Gallo, associate professor of dermatology and pediatrics at the University of California - San Diego and Dr. Masamoto Murakami, postdoctoral scientist, Veterans Medical Research Center.

Whether certain proteins made by the immune system may trigger the onset of rosacea is the subject of continuing research sponsored by National Rosacea Society research grants. While acting to protect the body, the proteins also may trigger some of rosacea's symptoms, the researchers hypothesize.

"If this theory proves true — that rosacea is in some way a disorder of the innate immune system — then completely new therapeutic approaches can be developed to treat this disease," Dr. Gallo said.

The immune system, which is responsible for the body's ability to combat illness and infection, produces its own antibacterial agents that fight disease and heal wounds, Dr. Gallo said. These natural substances act by eliminating the presence of harmful bacteria and activating other parts of a complex immune reaction. Either irritation or infection may stimulate the production of these proteins, he noted.

Dr. Gallo's laboratory is investigating whether the immune system response, including the expression of a natural protein called a cathelicidin, may cause some of the signs and symptoms of rosacea.

In their initial study, Dr. Gallo and his colleagues found an abnormally high level of cathelicidins upon histopathological staining in the skin of patients with rosacea. They further noted that some hallmarks of rosacea, including inflammation and growth of blood vessels, are associated with cathelicidins.

In a second study, the researchers are now investigating whether the redness, inflammation and blood vessel growth of rosacea are a result of an abnormal expression of this natural antibiotic. Using immunohistochemistry and quantitative polymerase chain reactions, Dr. Gallo and his colleagues found that in rosacea the chronic production of cathelicidins appears to be ineffective in inhibiting the spread of bacteria, and may instead simply trigger rosacea's signs and symptoms.

The researchers plan to further test their hypothesis by examining the effect of cathelicidins in mice and on human blood cells.

Publication of results: Yamasaki K, Barden A, Taylor K, Wong C, Ohtake T, Murakami M, Gallo RL. Expression and potential pathological role of cathelicidin expression in rosacea [abstract]. The Journal of Investigative Dermatology 2004;122:A51. Abstract 301.

The role of nitric oxide in rosacea Dr. Ethan A. Lerner, associate professor of Dermatology, Harvard Medical School.

In research funded by the National Rosacea Society, Dr. Lerner examined the potential contribution of nitric oxide to the redness and inflammation of rosacea. Nitric oxide is a gas produced naturally in nearly all of the body's cells and is used by the nervous, immune and cardiovascular systems. Because nitric oxide is known to make blood vessels dilate, it was hypothesized that it may play a role in rosacea.

The study aimed to test for the presence of nitric oxide synthase (NOS), a nitric oxide-producing enzyme, and the gene that creates NOS in the skin of rosacea patients through in situ hybridization and immunoperoxidase.

The in situ hybridization test was inconclusive; the researchers had difficulty obtaining clean results from the probes, and high background levels made it difficult to isolate NOS readings.

In the immunoperoxidase test, stains of biopsies taken from the skin of rosacea patients showed a normal amount of NOS. This could be interpreted as indicating that nitric oxide is not a significant factor in rosacea. However, Dr. Lerner believes that different types and severities of rosacea should be tested before the molecule can be completely ruled out.

The researchers also determined how much of a known nitric oxide inhibitor is absorbed through the skin, so that the effects of suppressing nitric oxide might be tested.

In other research, Dr. Lerner is developing a mouse model of what happens in human skin when too much nitric oxide is present. He is attempting to produce transgenic mice in which the gene for NOS is expressed in the skin under the control of a promoter, so that application of a topical compound will cause production of nitric oxide. Among the potential outcomes to be observed is whether too much nitric oxide produces any signs of rosacea.

Influence of skin temperature on bacteria in rosacea Dr. Mark V. Dahl, chairman of Dermatology, Mayo Clinic Scottsdale, and Dr. Patrick M. Schlievert, professor of Microbiology, University of Minnesota Medical School.

The greater warmth of the facial skin of rosacea sufferers may play a role in triggering the unsightly bumps and pimples that are common signs of this disorder, according to a new study funded by a grant from the National Rosacea Society and reported at the 2001 annual meeting of the Society for Investigative Dermatology.

In the completed study, Drs. Dahl and Schlievert found that at higher temperatures bacteria from the facial skin of both rosacea patients and people without rosacea released substantially more potentially toxic substances. The study noted that the surface temperature of facial skin in rosacea patients may be warmer than normal skin due to redness and flushing, and the resulting increase in toxic substances may lead to the bumps and pimples often associated with the disorder.

"Researchers have long wondered whether bacteria may be responsible for the inflammation, papules and pustules of rosacea, especially because these signs can be successfully treated with oral and topical antibiotics that destroy bacteria as well as reduce inflammation," Dr. Dahl said.

The researchers cultured samples of Staphylococcus bacteria from the pustules (pimples) of four untreated rosacea patients and the skin surface of four people without rosacea at both 86 and 99 degrees Fahrenheit. They found that, while the bacteria grew at the same rate in both the lower and higher temperatures, at the higher temperature the samples produced larger amounts of potentially toxic proteins.

In addition, some substances were secreted by the bacteria at the higher temperature that were not produced at the lower one. This included a type of enzyme known as a lipase — a protein that acts to speed chemical reactions — that may break down oils on the skin surface, potentially leading to blemishes and inflammation. Moreover, while all samples from rosacea patients produced the lipase, half of the samples from people without rosacea did not.

Dr. Dahl described several possible interpretations of these study results. Common bacteria may have a tendency to generate more of these irritating substances at the higher temperatures encountered on the faces of people with rosacea. Also, they may generate different harmful materials at these higher temperatures. The nature of these materials or the amounts produced could trigger papules and pustules.

Dr. Dahl further noted that other bacteria might also behave differently on the warmer skin of rosacea patients.

"Our findings suggest that temperature may change the toxicity of many types of common bacteria, opening a whole new avenue of research into this widespread but poorly understood disorder," Dr. Dahl said.

Publication of results: Dahl MV, Ross AJ, Schlievert PM. Temperature regulates bacterial protein production: possible role in rosacea. Journal of the American Academy of Dermatology 2004;50:266-272.

Endoglin expression in dermal endothelial cells Dr. Robert A. Swerlick, associate professor of Dermatology, Emory School of Medicine.

Sunlight and heat do not appear to cause visible blood vessels (telangiectasia) in rosacea patients by decreasing endoglin production, according to a study funded by a grant from the National Rosacea Society aimed at finding a cause for this common sign of rosacea.

Endoglin is a protein in human skin cells that plays a role in vascular development. In the completed study, Dr. Swerlick and other researchers had hypothesized that changes in endoglin expression in skin cells may cause telangiectasia in rosacea patients in a manner similar to that seen in a disorder known as hereditary hemorrhagic telangiectasia. They tested whether exposure to such environmental factors as sunlight and heat, which are often reported as rosacea triggers, may depress endoglin expression to allow the formation of visible blood vessels in rosacea patients. No effect was found from heat or sunlight on the expression of endoglin after blinded comparisons of skin samples stained for immunofluorescent identification of activity. The results of the study therefore suggest that no such relationships exist in rosacea.

The role of vascular endothelial growth factor in rosacea Dr. Mina Yaar, professor of Dermatology, Boston University School of Medicine.

Sun exposure appears to trigger a substance in the body that may lead to the visible blood vessels that often appear with rosacea, a conspicuous facial disorder now estimated to affect 14 million Americans, according to research funded by the National Rosacea Society and reported at the 2002 annual meeting of the Society for Investigative Dermatology.

"Our initial study showed that sunlight may indeed have a role in causing rosacea," said Dr. Marita Kosmadaki, research fellow, Department of Dermatology, Boston University, who presented results of her research with Dr. Mina Yaar, professor of dermatology at Boston University.

Drs. Yaar and Kosmadaki found that exposure to ultraviolet (UV) radiation — a component of sunlight — led to the production of vascular endothelial growth factor (VEGF), a substance that has been linked to the development of visible blood vessels (telangiectasia).

"The melanin in the skin of darker-skinned individuals appears to make it difficult for UV radiation to reach the lower layers of the skin," Dr. Kosmadaki noted. "As a result, in darker-skinned individuals VEGF would tend to be induced only in the upper skin layers, and hence would not affect the blood vessels. In contrast, sufficient ultraviolet rays could induce VEGF synthesis in the deeper skin layers in fair-skinned individuals."

Because other researchers had found the production of VEGF can be triggered by another molecule called tumor necrosis factor (TNF), Drs. Yaar and Kosmadaki hypothesized that the UV radiation first induced the production of TNF, and its release in turn led to the synthesis of VEGF.

They then tested whether a hexapeptide, which binds TNF and cancels its effect, would block VEGF production and leave blood vessels unaffected. However, their research found that blocking this single pathway was ineffective in preventing the production of VEGF.

"Our findings have shed new light on the potential pathogenesis of this vascular component of rosacea," Dr. Kosmadaki said. "It appears that sun-induced VEGF may play a significant role in rosacea, and its production process seems to involve factors other than TNF. This opens the way for further research that may lead to substantial improvements in treatment or prevention."

Publication of results: Kosmadaki MG, Yaar M, Arble BL, Gilchrest BA. UV induces VEGF through a TNF-alpha independent pathway. Federation of American Societies for Experimental Biology Journal 2003;17:446-448.

Phone: 1-847-382-8971 Email:   [email protected] National Rosacea Society 4619 N. Ravenswood Ave., Ste. 103 Chicago, IL 60640

Our Mission

The National Rosacea Society is a 501(c)(3) non-profit organization whose mission is to improve the lives of people with rosacea by raising awareness, providing public health information and supporting medical research on this widespread but poorly understood disorder. The information the Society provides should not be considered medical advice, nor is it intended to replace consultation with a qualified physician. The Society does not evaluate, endorse or recommend any particular medications, products, equipment or treatments. Rosacea may vary substantially from one patient to another, and treatment must be tailored by a physician for each individual case. For more information, visit About Us .

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• v.8(10); 2022 Oct

Current research and clinical trends in rosacea pathogenesis

a Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China

b Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, 410013, China

c Xiangya School of Medicine, Central South University, Changsha, 410013, China

Dan-Yi Zhang

Yi-chao yang, sheng-yuan zheng, xin-xing wan.

d Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, 410013, China

e Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China

f National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China

Rong-Hua Yang

g Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China

h Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha, 410008, China

i Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, 571199, China

Associated Data

Rosacea is a common and complex chronic inflammatory skin disorder, the pathophysiology and etiology of which remain unclear. Recently, significant new insights into rosacea pathogenesis have enriched and reshaped our understanding of the disorder. A systematic analysis based on current studies will facilitate further research on rosacea pathogenesis.

To establish an international core outcome and knowledge system of rosacea pathogenesis and develop a challenge, trend and hot spot analysis set for research and clinical studies on rosacea using bibliometric analysis and data mining.

A search of the WoS, and PubMed, MEDLINE, Embase and Cochrane collaboration databases was conducted to perform visual bibliometric and data analysis.

A total of 2,654 studies were used for the visualization and 302 of the 6,769 outcomes for data analysis. It reveals an increased trend line in the field of rosacea, in which its fast-growing pathogenesis attracted attention closely related to risk, comorbidity and therapeutic strategies. The rosacea pathogenesis has undergone the great development on immunology, microorganisms, genes, skin barriers and neurogenetics. The major of studies have focused on immune and microorganisms. And keyword visualization and data analyses demonstrated the cross-talk between cells or each aspect of pathogenesis, such as gene-gene or gene-environment interactions, and neurological mechanisms associated with the rosacea phenotype warrant further research.

Limitations

Inherent limitations of bibliometrics; and reliance on research and retrospective studies.

Conclusions

The understanding of rosacea's pathogenesis has been significantly enhanced with the improved technology and multidisciplinary integration, but high-quality, strong evidence in favor of genomic and neurogenic requires further research combined with a better understanding of risks and comorbidities to guide clinical practice.

Graphical abstract

Rosacea; Pathogenesis; Bibliometric analysis; Data mining study; Risk factors; Comorbidity; Treatment.

1. Introduction

Rosacea is a complex chronic inflammatory facial skin disease that can have an adverse effect on the life quality of people worldwide. The prevalence of rosacea among people worldwide incidences peaks as high as 18% [ 1 , 2 ], with estimates as high as 40 million cases, mostly in people aged between 30 and 50 [ 3 , 4 ]. Rosacea primarily affects the cheeks, nose, chin, and forehead with transient or persistent facial erythema, telangiectasia, papules, pustules, and recurrent flushing [ 5 ]. These pathological changes can lead to significant physical and mental discomfort, such as disfiguring manifestations, loss of sight in ocular rosacea, embarrassment, low self-esteem, and social phobia. Therefore, there is an urgent need for global research to develop better and more comprehensive management of rosacea, including its pathogenesis, risk factors, comorbidities, and treatment.

Although the etiology of rosacea is poorly understood, genetic factors, neurogenic dysregulation, immune systems dysregulation, microorganisms, barrier function impairment, and inflammatory response may play a major role in the development of rosacea [ 6 , 7 , 8 ]. In addition, a series of risk factors, comorbidities and specific treatments have also provided supplementary evidence for rosacea pathogenesis. For example, triggers that exacerbate the disorder ( e.g., heat, stress) may suggest a neurogenic relationship with rosacea [ 7 ]. And a significant association with psychiatric, neurological, metabolic and gastrointestinal diseases of rosacea are closely related to neurogenic dysregulation and microorganisms [ 9 , 10 ]. Based on these findings, various advancements in the rosacea pathogenesis system have been made.

Recognizing and addressing the pathogenesis system are critical to improve the outcomes of rosacea management [ 11 ]. However, updated and systematic data on the rosacea's pathogenesis are still relatively sparse, which has not been thoroughly evaluated through comprehensive evidence or even through information on risks, comorbidities and treatments. Moreover, the development, research emphasis, challenges and prospects of rosacea research have been poor to date. Thus, the aim of this article was to establish a knowledge system of rosacea's pathogenesis system through a series of comprehensive studies. Notably, we also performed a trend analysis and insight setting for the guidelines on rosacea research and clinical study according to the pathogenesis system. Meanwhile, the noted management is highlighted for patients with rosacea.

2. Data and methods

2.1. data strategy and selection criteria for bibliometric study.

Literature data for this bibliometrics study were retrieved from the Web of Science (WoS) Core Collection. The WoS Core Collection contains several important index types, including Science Citation Index Expanded (SCIE), Social Science Citation Index (SSCI) and Emerging Sources Citation Index (ESCI). For a more comprehensive search of evidence on rosacea pathogenesis, we performed a thorough search and then manual classification to avoid missing information.

To perform a systematic analysis of rosacea, we chose articles, reviews and letters for inclusion in a visualization analysis. The terms ‘Rosacea’ and ‘Pathogenesis’ were used in the MeSH ( https://www.ncbi.nlm.nih.gov/mesh ) search, whereas ‘Rosacea’ and ‘Pathogenesis’ were represented by other expressions, such as ‘Rhinophyma’ and ‘etiology’, respectively. The search strategy used was as follows (TS=(rosacea) OR TS=(Rhinophyma)) AND (LA=(“ENGLISH”)) AND (DT= (“ARTICLE” OR “REVIEW” OR “LETTER”)); AND WEB OF SCIENCE INDEX (WOS. SCI), and time span of 1992–01-01 to 2022-01-01 ( Figure 1 ).

Systematic literature search and outcome identification.

2.2. Data strategy and inclusion/exclusion criteria for data mining

We used a systematic approach to search the following databases: PubMed, MEDLINE, Embase and Cochrane collaboration databases with the search terms ‘Rosacea’ or ‘Rhinophyma’. The article type was limited to English-language studies dated to 2022-01-01, with no limits on participant age, sex or type. The retrieval strategy of each database was customized according to the usage standard of the database and the scale of the retrieved documents. After the exclusion of repeated articles, a manual review of the citations from these articles was performed to identify additional articles by screening titles, abstracts and manuscripts. The literature screening process is shown in Figure 1 , including search strategy and inclusion/exclusion criteria.

2.3. Data extraction and methodology

As for data extraction, the following information for rosacea pathogenesis was extracted by two investigators (XMH and ZXL) independently: first author's last name, year of publication, geographical region, study design, sample type, sample size, subtyping of rosacea, cell/bacteria culture/mice used in research, the key conclusion. while these information for risk factors/comorbidity/therapy was added as follow: mean age, gender, number of patient/exposure population-controls, adjusted risk estimate, variables adjusted in the multivariable analysis, etc . Moreover, publication bias was assessed using the Egger's test and visual inspection of funnel plots (Supplemental Figure 1). These statistical analyses were carried out with the ‘meta’ package of R.

The visualization analysis of the retrieval characteristics of rosacea included the distribution of publication years, countries and regions, organizations, journals, core authors, keywords and key references. Bibliometric analysis and network visualization were performed with VOSviewer (Version 1.6.14; https://www.vosviewer.com/download#downloadvosviewer ) and CiteSpace (Version 6.1. R2; https://sourceforge . net/projects/citespace/files/latest/download). Microsoft Excel 2010 was used to assess the distribution of publication years. The Gunn map ( http://lert.co.nz/map/ ) online world map was used to evaluate the distribution of countries and regions. Ranking was performed using the standard competition ranking method. Microsoft Excel software was utilized for data collection and analysis, and Adobe Illustrator CS6 was used for figure summary as Figures  5 , ​ ,6, 6 , and ​ and7 7 .

The timeline of some key discoveries in the field of the pathogenesis of rosacea. The timeline shows different aspects of pathogenesis in different colors as follows: green—immune, red—neurogenic, orange—barrier, purple—gene, blue—microorganisms. Part of the detailed development has occurred in topics such as cathelicidine/LL-37, mast cells and genes. A guideline with a vital role in the development of rosacea is shown in the second timeline below. MMPs, matrix metalloproteinases; IL-1 β, interleukin-1 beta; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor; HLA, human leukocyte antigen; ncRNA, noncoding RNA; mTOR, mammalian target of rapamycin; STAT, signal transducers and activators of transcription; H. pylori: Helicobacter pylori; TACR3, tachykinin receptor 3; TEWL: transepidermal water loss; TRPV, transient receptor potential ion channels of vanilloid type; B. oleronius, Bacillus oleronius; CGRP, calcitonin gene-related protein; GC, glucocorticoids; UVR, ultraviolet radiation. (The primary data for this analysis are shown in Tables S 1–6.)

Mechanisms known to contribute to the pathophysiology of rosacea. The cathelicidin could be cleaved into its active peptide form, LL-37, by KLK5 or protease 3. These mutant forms of LL-37 play a role in inflammation and angiogenesis, which contribute to the clinical manifestations seen in rosacea. KLK5 is transformed from a proenzyme to an active enzyme by MMPs. TLR2 signaling could be triggered via multiple factors, such as ultraviolet (UV) light, reactive oxygen species or microbes and Demodex/mite , which again leads to increased levels of LL-37. Moreover, UV could activate VEGF, further contributing to the clinical manifestations of rosacea. Additionally, mast cells could produce LL-37 and other cytokines to promote inflammation in rosacea. Other triggers, such as spicy food, stress, exercise, and heat, have been shown to activate TRPV/TRPA1. Rosacea seems to be a disease with systemic implications rather than a localized skin disease as previously thought. Whether these mechanisms are involved in the systemic implications needs further study. Abbreviations: KLK5: Kallikrein 5; MMPs: Matrix metalloproteinases; TLR2: Toll-like receptor 2; UV: Ultraviolet; VEGF: Vascular endothelial growth factor; TRPV: Transient receptor potential vanilloid; TRPA1: Transient receptor potential ankyrin 1.

Establishment of the systemic pathogenesis of rosacea. The distribution of each subitem in the studies of rosacea pathogenesis according to publications is also shown (primary data for this analysis is shown in Table S9). Comorbidities and risk factors share distinct pathogenetic associations with rosacea. For example, rosacea comorbidities, such as autoimmune disorders, may be related to immune, genetic, barrier and other factors. The risk factors, such as heat, sun, and spicy food, suggest a relationship between rosacea and neurogenetic pathogenesis.

3.1. Bibliometric analysis

3.1.1. an increased trend line of publications in the field of rosacea.

There were 1,980 (74.604%) articles, 350 (13.188%) reviews and 324 (12.208%) letters among the 2,654 publications. The chronological distribution of published documents is shown in Figure 2 . The trend line demonstrates that the number of documents increased exponentially. The line chart illustrates that the number of documents increased relatively slowly from 1902 (n = 1, 0.038%) to 2002 (n = 33, 1.247%). Overall, the number of publications showed a sharply increasing trend from 2002 (with the largest sequential growth rate, 73%) onward, and the National Rosacea Society Expert Committee has developed a classification system and diagnostic standard to guiding clinicians and researchers. By 2020 (n = 262, 9.902%), the number of publications reached a peak. With a more standardized diagnosis as well as the improvement of aesthetics and quality of life, rosacea has attracted increasing attention worldwide, indicating that it will gradually become a research hotspot.

Distribution of publications on rosacea according to year. The number of publications increased slowly from 1902 to 2002. Overall, the number of publications showed an increasing trend in volatility from 2002 onward to a peak in 2020 (primary data for this analysis are shown in Table S7).

3.1.2. Rosacea is regarded as a universal and global topic according to its spatial distribution

According to the statistical analysis, 2,654 documents were published by research groups from 86 countries and regions using full counting analysis. The top 10 most prolific countries and regions have been shown in Table 1 . The country with the largest number of documents was the United States (n = 927, 34.93%), followed by Turkey (n = 211, 7.95%), China (n = 210, 7.91%), and Germany (n = 205, 8.48%). Besides the number of publications, the United States also ranked the first according to the citation and centrality. The countries and regions with the strongest citation bursts are also shown in Table 1 . Among them, China had the highest burst strength of 23.76. The duration of burst began in 2019 and ended in 2022, indicating that there were many researchers studying rosacea in China during 2019–2022. Many of countries have raised attention to rosacea from 1999 and recently more and more countries have also emerged, such as China and France. This spatial distribution maybe closely to the reported a varied prevalence of rosacea in people with skin of color from 1%- 22% [ 4 ]. Detailly, the research on the racial/ethnic distribution of patients with rosacea has been reported that 3.9% of rosacea patients were Hispanic or Latino, 2.3% were Asian or Pacific Islander, and 2% were black according to the US National Ambulatory Medical Care Survey (1993–2010) [ 12 ]. And other reasons may also contribute to this phenomenon, such as economy, technologic development, humanities and so on.

Table 1

Top 10 most productive countries and regions with publications on rosacea (2022-01-01).

Note: a strong citation burst indicates that a variable undergoes a great change in a short period of time.

3.1.3. The pathogenesis of rosacea has attracted attention according to the citations

Among the total documents (n = 2,654), 40 met the threshold for vitalization analysis. According to the citation analysis of documents (n = 2,581), which reflects the number of times the documents were cited, we listed the top 10 most highly cited documents in Table 2 . The range of the number of citations was 218–531. The top highly cited references were Hengge (2006), Wilkin (2002), Solomon (2001a), Yamasaki (2007), Sapadin (2006), Crawford (2004), and Bamford (2004), which had the highest number of citations, indicating that they were the most influential studies associated with rosacea. In addition, a systematic review and updating of international conferences on rosacea were likely cited many times.

Table 2

List of the top 10 most cited articles in rosacea (2022-01-01).

∗ marked the document related to pathogenesis of rosacea. IL-1alpha, Interleukin 1alpha; TLR2, Toll-like receptor 2.

Half of these studies were related to pathogenetic mechanisms, such as “ Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry eye disease ”, which was ranked third and cited 500 times; “ Increased serine protease activity and cathelicidin promote skin inflammation in rosacea ”, ranked fourth and cited 488 times; and “ Rosacea: I. Etiology, pathogenesis, and subtype classification ”, ranked sixth and cited 334 times. Notably, the six research articles have focused on the pathogenetic mechanism [ 13 , 14 , 15 , 16 , 17 , 18 ]. All of this evidence suggests that pathogenesis plays a vital role in the field of rosacea and has attracted attention for years as a hotspot [ 13 , 14 , 15 , 16 , 17 , 18 ].

3.1.4. Pathogenesis as a new fast-growing rosacea subject according to the keywords

A total of 6,948 keywords were retrieved from 2,654 documents, and 100 met the threshold. The network visualization map shows the co-occurrence relations of keywords ( Figure 3 ). The size of the circle indicates the occurrence of keywords. As shown in Figure 3 , the high-frequency keywords include rosacea, skin, and pathogenesis. The average publication year of these three keywords is from 2012 to 2014. Furthermore, it also shows a fast-growing part that has developed in recent years, as the node in yellow indicates in Figure 3 . As can be seen, in the last 5 years, an increasing number of researchers have given attention to cathelicidin, cytokines, immunity, mites, inflammation, pathophysiology, risk, and comorbidity in rosacea, indicating that pathophysiological factors have attracted attention as the focus of future research. Additionally, the management of rosacea, such as therapy, telangiectasia, and pulsed dye laser therapy, is a conspicuous aspect of rosacea research. All of this evidence suggests that it is a hotspot, and many scholars have devoted themselves to researching it.

Co-occurrence analysis of keywords the keywords. The analysis method was Linlog/modularity. The weight was recorded. The color of the circle represents the average publication year. The red arrows are pathologically relevant, while the blue arrows are pathogenetic supporting evidence.

4. Results of data mining on rosacea

4.1. each of the core components of pathogenesis tends to increase.

An increasing amount of evidence on rosacea etiology suggests that microorganisms (75, 31.9%), immune system (63, 26.8%), abnormal barrier function (33, 14.0%), gene (16, 6.8%), neurogenic (17, 7.2%), and other (30, 12.8%) factors may be genetic components. Additionally, the annual incidence of each factor is shown in Figure 4 . The etiologic research on the immune system factors related to rosacea started in 1984, fluctuated rapidly in the last decade, and reached a peak in 2021. Additionally, research on microorganism etiology was conducted earlier, which is a major component (shown in orange in Figure 4 ) along with immune etiology (shown in blue in Figure 4 ). “Neurogenetic etiology” has been termed earlier but remains slow in progress. Abnormal barrier function and gene parts seem to be emerging aspects of rosacea pathogenesis and have increased in the literature in recent years.

Distribution of publications on the pathogenesis of rosacea according to year, and each contribution is also shown (primary data for this analysis are shown in Table S8).

Moreover, detailed information on the studies on each component has shown in Table S1-6 and detailly explained in discussion part, the subgroups including ( e.g ., the roles of Demodex and H. pylori in microorganisms), study design, key outcomes, and publication year (neurogenetic and genetic etiologies, and immune, microorganism, barrier and other components).

4.2. Risk factors show an interface mechanism in rosacea pathogenesis

We screened out the parts as supporting material for rosacea pathogenesis. The main related risk factors include habits ( e.g., facial cleansing, shower, make-up, sun exposure), which suggest an impaired barrier function may be related to rosacea; natural factors ( e.g., H. pylori , E. coli) associated with immunity and microorganisms; genetic factors ( e.g., skin type, family history and genetic mutations) associated with genes; and neuropsychiatric factors ( e.g ., stress) associated with neurogenic parts. The detailed study design, individuals and statistical indicators are shown in Table 3 .

Table 3

Risk factors as supporting evidence for rosacea pathogenesis.

Risk factors will include in P < 0.01. GSTM1, Glutathione-S-transferase μ-1; GSTT1, Glutathione S-transferase theta 1; WT, Wild type; GCs, Glucocorticoids; P/N, positive/negetive; DS, Description study; CC, Case control; CSS, Cross-sectional study; CR, Case report; F/M, Female/Male; PSQI, Pittsburgh sleep quality index; OR, Odds ratio; CI, Confidence intervals.

4.3. Comorbidities and treatment also as vital supporting material for rosacea pathogenesis

Several studies have shown that rosacea is related to systemic disease, which could also contribute to rosacea pathogenesis. The prevailing literature has reported comorbidity associations between rosacea and gastrointestinal disorders ( e.g ., irritable bowel syndrome (IBS), Crohn's disease), which proved the association with dysbacteriosis laterally. Notably, psychiatric diagnoses ( e.g., anxiety, depression) and neurological disorders ( e.g., Parkinson's disease, migraine, Alzheimer's disease) suggest a strong association between rosacea and neurogenic pathogenesis. More detailed information (study design, individuals and statistical indicators) is shown in Table 4 . Moreover, some of the treatments based on pathogenesis are also regarded as supporting evidence for the etiology of rosacea ( Table 5 ).

Table 4

Comorbidities as supporting evidence for rosacea pathogenesis.

Comorbidity will include in P < 0.01. FMS: Fibromyalgia syndrome; GERD: Gastroesophageal reflux disease; SIBO: Small intestinal bacterial overgrowth; MDD: Major depressive disorder; OCD: Obsessive–compulsive disorder; P/N: positive/negetive; CC: Case control; CSS: Cross-sectional study; F/M: Female/Male; OR: Odds ratio; CI: Confidence intervals; HR: Hazard ratio; IRR: incidence rate ratio.

Table 5

Treatment as supporting evidence for rosacea pathogenesis.

(KLK5, Kallikrein 5; MMP-3, Matrix metalloproteinase-3; VEGF, Vascular endothelial growth factor; mTORC1, Mechanistic target of rapamycin complex 1; TXA, Tranexamic acid; ART, Artemisinin; MLT, Melatonin; PGZ, Pioglitazone; MCs, Mast cells; TNF-α, Tumor necrosis factor α; TLR2, Toll-like receptor 2; IL-1α, Interleukin 1α; NEAT1, Nuclear-enriched abundant transcript ​1; SIBO, Small intestinal bacterial overgrowth; TRPV1, Transient receptor potential vanilloid; PPARγ, Peroxisome proliferator-activated receptor γ; PDE5i, Phosphodiesterase-5 inhibitors; ROS, Reactive oxygen species; GNP, Gold nanoparticles; CB1, Cinnamtannin B; HCQ, Hydroxychloroquine; ssON, Single-stranded oligonucleotide; SAGEs, Semi-synthetic glycosaminoglycan ethers; SOD3, Superoxide dismutase 3; DRG, Dermasence refining gel; mTORC1, Mechanistic target of rapamycin complex 1; AzA, Azelaic acid; DS, Description study; CC, Case control; RA, Research article; RCT, Randomized controlled trial; PPR, Papulopustular rosacea; OcR, Ocular rosacea; ETR, Erythematotelangiectatic rosacea; HCs, Human controls; ERK, Extracellular signal-regulated kinase; VD3, Vitamin D; NF-κB, Nuclear factor kappa-B; MAPK, Mitogen-activated protein kinase; LPND, yttrium-aluminum-garnet laser; SOCS3-ASK1-p38, Suppressor of cytokine signaling 3-apoptosis signal-regulating kinase 1-p38; HMGB-1, High mobility group box-1; RF, Radiofrequency; NO, nitric oxide.).

5. Discussion

Over the more than one hundred years of rosacea studies, the number of annual publications showed a sharply increasing trend from 2002, with the largest sequential growth rate onward and gradual increase in the last decade, reaching a peak in 2020 and 2021. The turning point in 2002 and 2004 may be related to the established standard for the classification system and diagnostic criteria by the National Rosacea Society Expert Committee [ 19 , 20 ]. To date, the complex pathogenesis of rosacea has been elucidated. The timeline of some key discoveries has summered in Figure 5 . Microorganisms have been found to be present early in rosacea pathogenesis, which develops with an increase in B. protein [ 18 ] and is associated with immunity and neurogenesis [ 21 , 22 ]. Immune dysregulation continues to increase as a result of various immune cells and cytokines [ 23 , 24 ]. An increasingly valued part, neurogenic dysregulation, has provided novel insight into rosacea pathogenesis [ 25 , 26 ]. Family history suggests the presence of a genetic factor in the pathogenesis of rosacea [ 27 , 28 ] and is enriched and elaborated to support other parts, such as immunity [ 29 ]. Several documents in the last two years may refer to emerging technologies (gene sequencing or single-cell sequencing, spatial transcriptomics, and other bioinformatics) and groups. Regardless, the increased curve trend of studies on rosacea suggests that an increasing number of researchers have become interested in rosacea, which indicates that there are still unsolved problems, such as pathogenesis.

Among the research on rosacea, pathogenesis seems to be a key part and a research hotspot. Among the top 10 highly cited documents, more than half of the documents addressed pathology-related studies, such as increased IL-1 expression [ 13 ], cathelicidin in skin inflammatory responses [ 14 ]. According to the keyword data, an increasing number of researchers have focused on pathogenesis-related items in the last 5 years. Further, we have summarized a systematic mechanistic pathway known to contribute to the pathophysiology of rosacea in Figure 6 .

5.1. Genetic factors

The increased evidence in individuals with rosacea suggests that there may be a genetic component of the disorder. Earlier, a family history of rosacea, skin type (Fitzpatrick IV), and specific genetic mutations (ApaI G/T) were reported as risk factors, which strongly suggests a genetic component of the disorder. Various genomic association studies have already identified some genes pointing to various pathogenetic terms, such as the intercellular adhesion molecule-1 ( ICAM-1 ) gene related to barrier function [ 30 ], glutathione S-transferase theta 1 ( GSTT1 ) and/or glutathione-S-transferase μ-1 ( GSTM1 ) and nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 ( NLRP3 ) gene related to immune and inflammation [ 31 , 32 , 33 ], human leukocyte antigen-DR alpha ( HLA-DRA ), butyrophilin-like 2 ( BTNL2 ) and signal transducer of activators of transcription ( STAT ) gene related to the immune [ 8 , 34 , 35 ]. Studies based on family, twin and regional factors (Celtic and Northern European descent) also suggest a genetic component of rosacea [ 29 , 36 ]. Moreover, genetic studies have been reported every year since 2015 and may continue to increase with emerging technologies ( e.g. , gene sequencing [ 37 ], omics analysis [ 38 ], other bioinformatics tools utilized in rosacea [ 39 ]). Further investigation will continue to focus on the mechanistic link between the gene variants identified in the rosacea phenotype [ 40 ]. Additionally, gene–gene ( e.g. , lncRNA-mRNA coexpression networks [ 41 ]) and gene–environment interactions ( e.g ., gene-ultraviolet) would be one of the focuses of intensive research studies. Finally, more research needs to be conducted on the causative genes, including their detailed functional feedback, for clinical applications.

5.2. Microorganisms

The percentages of studies related to microorganisms is extraordinarily large in the area of rosacea pathogenesis. According to our data, microbial pathogenesis can be divided into two parts: 1. Infection: Demodex/mite and H. pylori infection; 2. Dysbacteriosis: microorganisms in the skin, blood and gut.

The earlier study focused on descriptive research, has reported mite was only a highlighted risks [ 42 ]. Multiple studies have focused on the strong association of Demodex in deep pathogenesis, such as inflammatory stimulation [ 43 , 44 ], tissue degradation [ 45 ], targeted therapies [ 46 ]. Detailly, the mechanism may be related to Demodex -associated Bacillus proteins, which could involve in inositol 1,4,5-trisphosphate (IP3) pathway [ 21 ], leading to corneal scarring [ 47 ] or erythema [ 48 ]. However, the topic regarding the causality between Demodex/mite and rosacea is still controversial. Immune and skin barrier dysregulation in rosacea patients may also lead to pathological growth of Demodex/mite [ 49 ]. So, more recent studies have reported Demodex/mite as aggravated factors of rosacea [ 50 ]. Overall, causality needs to be further studied through close observation of rosacea patients through the entire development combined with basic studies and accurate testing methods.

The role of H. pylori in the rosacea's pathogenesis remains controversial, which is mostly reported as an aggravating factor in rosacea and the target therapy is beneficial [ 51 ]. Other dysbacteriosis or targeted therapies have also attracted attention as they relate to skin microorganisms (S epidermidis [ 52 ]) and intestinal flora (E. coli Nissle therapy [ 53 ]). However, some studies have conducted superficial difference analyses. Therefore, how to explain a deeper microorganism mechanism contributing to the progression of rosacea and how to address it remain challenges. Whether inner linkage is involved in systematic dysbacteriosis occurring in the blood, gut, and skin as axis also requires further investigation to guide systematic and maintenance treatment on rosacea and reduce recurrence [ 54 ].

5.3. Immune system dysregulation

Research on the immunology related to the rosacea pathogenesis has rapidly increased in recent years. In addition to the technologies, research models have been established to aid this effort (LL-37 induced rosacea-like traits in mice and various cells) [ 55 ]. LL-37 (Cathelicidin antimicrobial peptide) and kallikrein 5 (KLK5) may serve as the key contributors to the proinflammatory and proangiogenic effects, which are highly expressed in the skin of patients with rosacea. Recent studies may pay more attention to the integrated mechanism of their up/downstream molecules (e.g., NLRP3 inflammasome [ 56 ], IL-36γ [ 57 ], protease-activated receptor 2 (PAR-2) [ 58 ], mechanistic target of rapamycin complex 1 (mTORC1) [ 59 ]). Additionally, it has also reported high expression of toll-like receptor (TLR) family and matrix metalloproteinases (MMPs) in patients with rosacea. Specifically, TLR1/2 and TLR4 activation promoted inflammation [ 60 ], TLR2 gene expression was enhanced in glucocorticoid-induced rosacea [ 61 ], and the TLR signaling pathway was modulated by Demodex mites in rosacea progression [ 17 ].

Recent work has also focused on immune cells. An increased baseline number, activation and polarization of immune cells have been found in patients with rosacea ( e.g ., mast cells, dendritic cells, T cells, Langerhans cells, plasma cells, macrophages, neutrophils) [ 62 ]. For example, N2-polarized neutrophils reduce inflammation in rosacea by regulating vascular factors and proliferation of CD4 + cells [ 63 ]. A continued increasing trend may focus on more detailed and causative mechanisms, and a more complex co-network. Notably, these molecules have also contributed to diagnosis and treatment (e.g., doxycycline inhibited MMP [ 64 ], azelaic acid (AzA) inhibited KLK5 and TLR2 [ 65 ]). Thus, the pathogenesis of rosacea will also continue to be studied in relation to clinical applications.

5.4. Neurogenic dysregulation

Strong and universally accepted evidence suggests a potential pathogenesis of neurogenic dysregulation. For example, triggers (stress, spicy food and heat [ 66 ]) could be aggravating factors for rosacea. Comorbidity research also suggests a close relationship between neurogenic dysregulation and rosacea, such as psychosis (e.g., anxiety, depression) and neurological disorders (e.g., Parkinson's disease, Alzheimer's disease). Additionally, symptoms ( e.g ., erythema, itch, and pain) also refer to neurogenic disorders of rosacea. Although the term “neurogenic dysregulation” has been developed in relation to rosacea in the 20 th century, the pathogenesis mechanism has been difficult to elucidate, possibly due to limitations in technologies or the heterogeneity of the disease presentation. It has been found that some neurogenic events are regarded as vital components in patients with rosacea ( e.g ., sympathetic/axon reflex-mediated alterations [ 67 ], the neuropeptide calcitonin gene-related peptide (CGRP-α) [ 68 ], substance P [ 69 ], transient receptor potential vanilloid (TRPV) [ 70 ] and the vascular endothelial-derived growth factor (VEGF) family [ 71 ]). The detection of TRP channel activation is related to inflammatory skin conditions, itching, and pain [ 25 ]. TRPV2 and TRPV4 were found to colocalize with mast cells in rosacea patients [ 26 ]. It has also reported that ETR has shown a significantly increased immunolabeling of TRPV2/3 and gene expression of TRPV1, while an enhanced immunoreactivity for TRPV2/TRPV4 has been found in PPR, and TRPV3/4 phymatous rosacea [ 26 ]. Additionally, it has been found that the upregulation of TRPV4 induced by LL-37 depends on mas-related gene X2 ( MRGX2 ) activity related to inflammation in rosacea [ 72 ]. TRPV channels are regarded as a key role in a variety of sensory pathologies. It is closely related to the release of neuropeptides from sensory nerve by a rise in the cytosolic Ca 2+ concentration [ 73 ]. Various lines of evidence point to neurogenic dysregulation, but further studies are needed to elucidate the mechanisms underlying this association using novel technologies, such as optogenetics, which leads to specific gene expression and gene product trafficking with subcellular precision [ 74 ], used in skin pathogens [ 75 ].

5.5. Inflammation and/or oxidative stress

Interestingly, a large number of studies are related to inflammation and/or ROS, which may be an indispensable event of rosacea. A high rate of inflammatory response has been found in subjects with rosacea ( e.g., follicular inflammatory reactions [ 76 ], the high-expressed cytokines IL-17 [ 77 ] and IL-1β [ 38 ]). It seems to be a response or a trigger to immune, microorganisms, and neurogenic dysregulation progression. Thus, these studies have further illuminated the detailed mechanism or triggers of inflammation related to serine protease activity and cathelicidin [ 14 ], immune cell infiltration [ 78 ], and Demodex mite infection [ 79 ]. For instance, mast cell proteases can recruit other immune cells through an inflammatory response, causing vasodilation and angiogenesis [ 80 ]. As for first-line strategy, AzA involves the specific activation of peroxisome proliferator-activated receptor γ (PPARγ), which plays a relevant role in inflammation and even in aging processes [ 81 ].

5.6. Abnormal barrier function

After suffering from those pathogenetic factors, skin may be dysfunctional featuring increased TEWL, decreased stratum corneum hydration [ 82 ], and collagen content [ 83 ], which is closely related to ICAM-1 and claudins (CLDNs, the main components of tight junctions constituting the major barrier) [ 84 ]. Thus, various creams and cleaners, such as Cetaphil PRO Redness Control Night Repair Cream, focus on repairing the skin barrier [ 85 ]. More related factors have been identified ( e.g ., UV/sun exposure, Vitamin D, and hormones) and are aiding for therapeutic guidelines.

5.7. Risk factors for pathogenesis

Based on the common triggers for rosacea induction or exacerbation, it may be regarded as an intuitive theory of its macrolevel role in the pathogenesis of rosacea. Current research on risk factors contributing to the disease etiology is focusing on molecular mechanisms. Based on our data, cleansing habits and skin care support barrier function. However, cleansing at a high frequency or with a machine could mechanically break the walls of stem cells [ 86 ]. Many studies have been conducted on each of these topics. Risk factors may serve as a guideline and initial factor for pathogenesis studies.

As shown in Table 3 , some of the outcomes of risk factors are controversial, such as whether spicy food is a positive risk factor for rosacea. In other words, there may be no specific risk factors associated with rosacea, and a large population-based study is needed to confirm this hypothesis. Additionally, it is important to recognize the control populations included in the study, which should be properly matched in terms of other factors. These factors may be known to influence each other or the rosacea phenotype, such as age, sex, body mass index (BMI), skin type, family history, related food, drug use, and sun exposure. Additionally, the risk factors for rosacea may vary with the phenotypic subtype, so we emphasize the importance of clear subtype inclusion and the related mechanisms in future studies. Further studies are needed to elucidate the mechanisms underlying this association.

5.8. Comorbidities of pathogenesis

In recent years (especially in 2021), some observational evidence has shown that patients with rosacea have a higher risk of developing various comorbidities, which also highlights the pathogenesis progression in rosacea ( Table 4 ). Regarding gastrointestinal disorders, almost all studies reported a positive relationship with rosacea, such as celiac disease, Crohn's disease, and irritable bowel syndrome (IBS). This can be understood in the context of the microbial pathogenesis of rosacea, which contributes to gastrointestinal disorders, such as H. pylori infection and dysbiosis of intestinal flora (i.e., small intestinal bacterial overgrowth (SIBO)). Psychiatric and neurological disorders have also been reported as positive comorbidities of rosacea (except dementia schizophrenia and migraine), which provides supplementary evidence for neurogenic dysregulation of pathogenesis in rosacea. Studies on rosacea comorbidities may continue to increase, combined with their pathogenetic pathways. However, many more concerns remain for continued research: 1) To date, association studies have failed to identify causal relationships between rosacea and other diseases. For example, rosacea could exert an adverse effect on quality of life, leading to psychiatric disorders. Meanwhile, anxiety disorders and depression may trigger or worsen rosacea. 2) The relationship between some diseases involving a particular system, such as Parkinson's disease in neurological system disorder, could not prove an overall association between the system disease and rosacea. 3) Whether identified comorbidities are positive or negative still needs to be further studied, such as migraine and schizophrenia.

6. Conclusion

Overall, the pathogenesis of rosacea has attracted increasing attention due to the complex interplay and/or co-network of genetic, microorganism, immunological, neurogenic, and barrier factors, further illustrating the chronic rather than acute nature of this inflammatory disease. We have provided a summary of the establishment of the systemic pathogenesis of rosacea in Figure 7 . Various factors, such as risk factors and comorbidities, also contribute to the pathogenesis of rosacea. Notably, a growing body of evidence suggests that the pathogenesis of rosacea may play a vital role in systematic pathological changes, as well as in a systemic origin, or be a marker for increased/decreased risk of systemic disease.

7. Limitations

Limited research models of rosacea; diagnostic testing of patients; patient selection protocols; possible confounding factors; non-standardized research data collection and reporting across studies; reliance on research and retrospective studies in the WoS, PubMed, MEDLINE, Embase and Cochrane collaboration databases. Inherent limitations of bibliometrics were reported in others [ 87 , 88 , 89 , 90 , 91 , 92 , 93 ].

Declarations

Author contribution statement.

Xi-min Hu, Li Ji, Rong-hua Yang and Kun Xiong: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper.

Zhi-xin Li, Dan-yi Zhang, Yi-chao Yang, Sheng-yuan Zheng, Qi Zhang and Xin-xing Wan: Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.

Funding statement

Ji Li was supported by National Key Research and Development Program of China [2021YFF1201200].

Kun Xiong was supported by National Natural Science Foundation of China [81971891; 82172196; 81772134].

Rong-hua Yang was supported by Applied Basic Research Key Project of Yunnan [2021A1515011453], Basic and Applied Basic Research Foundation of Guangdong Province [2022A1515012160], Key Laboratory of Medical Electrophysiology of Ministry of Education [KLET-202108].

Dr. Xi-min Hu was supported by National College Students Innovation and Entrepreneurship Training Program [S20210026020013].

Declaration of interest's statement

The authors declare no conflict of interest.

Additional information

No additional information is available for this paper.

Acknowledgements

We would like to thank American Journal Experts (AJE) ( http://www.aje.com ) for English language editing.

Appendix A. Supplementary data

The following is the supplementary data related to this article: