Rosacea is a chronic inflammatory disease that occurs in the middle of the face and has a complex etiopathogenesis involving immunological changes and neurovascular dysregulation. The main characteristic of rosacea is facial erythema, which presents as flushing, persistent erythema, telangiectasia, and erythema around inflammatory lesions. There are two forms of rosacea-associated erythema.1 One is inflammatory erythema, which may be related to temporary vasodilation resulting from the release of inflammatory factors after Demodex infection; the other is non-inflammatory erythema, which may be associated with continuous vasomotor dysfunction. Rosacea is a continuous inflammatory process, erythema may be the initial sign of underlying inflammation caused by Demodex infection and therefore requires treatment.2 Treatment approaches for rosacea-related erythema vary in accordance with the causes.
Rosacea-associated erythema has a negative impact on quality of life. Although there is no cure for rosacea-related erythema, there are numerous therapeutic options available that achieve satisfactory responses. PubMed and China National Knowledge Infrastructure (CNKI) database were searched from 2015 to 2020 for relevant articles published in the English or Chinese language, using a combination of following keywords “(rosacea or erythematotelangiectatic rosacea) and (treatment or management); rosacea and (erythema or flushing)”. Four researchers screened titles and abstracts, and then reviewed full-text for inclusion. Herein, we summarize the latest advances in the treatment of rosacea-related erythema.
All patients with rosacea should pay extra attention to gentle skin care. According to the Global Rosacea Consensus, skin care should include daily gentle cleaning, application of sunscreen with a sun protection factor ≥30, and use of high-quality moisturizing cream.3 Patients with rosacea should select a sunscreen that contains inorganic mineral products, such as titanium dioxide or zinc oxide, which do not generate heat or cause chemical stimulation. Moisturizing cream relieves dry skin, improves skin elasticity, and repairs and maintains the skin barrier, and can be used in conjunction with other treatments. The daily use of a whitening moisturizing cream with a sunscreen function reportedly significantly relieves and covers facial erythema, and is well tolerated by patients.4 According to data from the National Rosacea Society,5 the most common erythema triggers are sun exposure, emotional stress, and an overly high or low environmental temperature. Avoidance of the factors affecting the individual patient may help maintain remission.
Treatments for inflammatory erythema
Demodex infection causes the release of cytokines and inflammatory mediators that cause a series of clinical manifestations, including facial flushing, erythema, papules, pustules, and other skin problems. Acaricidal therapy kills the Demodex mites and decreases the subsequent inflammation and related symptoms, including persistent erythema. Mild erythema may be completely or almost completely resolved after mite eradication. For more severe erythema, acaricidal treatment might only slightly relieve the symptoms, but is useful because subsequent light treatment may be better tolerated, without the potential for flare-ups.2 Representative drugs are benzyl benzoate, ivermectin, and metronidazole. The US Food and Drug Administration (FDA) approved the use of 1% metroni-dazole emulsion to treat rosacea-associated erythema and inflammatory lesions. However, it is not effective for telangiectasias. Ivermectin is reportedly superior to metronidazole in terms of efficacy, continuous treatment effect, and recurrence rate.6
Azelaic acid is effective in treating rosacea-associated erythema because of its inhibition of neutrophil functions and the generation of reactive oxygen species. A small number of patients may initially feel itching, burning, and tingling, but these symptoms are generally mild and cease with time. The China Consensus recommends topical azelaic acid as the first-line topical treatment for persistent erythema.7 The use of 15% azelaic acid can alleviate erythema around inflammatory lesions such as papules and pustules, while there is no clinical evidence to confirm it is effective to treat non-inflammatory erythema.8
Calcineurin inhibitors act selectively on T cells and mast cells to prevent the production and release of cytokines and other inflammatory mediators, and achieve a better effect in treating erythema than papular pustules.9 However, calcineurin inhibitors have no effect on telangiectasias. Although calcineurin inhibitors are effective in the treatment of inflammatory erythema, long-term use might induce rosacea-like lesions,10 possibly due to the suppression of immune function and cytokine transcription. Therefore, calcineurin inhibitors should generally not be used for longer than 2 weeks.7 Adverse reactions such as worsening erythema, burning sensation, and dryness may manifest in the first few days, but generally disappear with time.
Antimicrobial peptide is an inflammatory factor that causes the proliferation of blood vessels, resulting in facial erythema. Doxycycline controls facial erythema by indirectly inhibiting the production of antimicrobial peptide. The FDA has approved the use of sub-antimicrobial doses of oral doxycycline (40 mg) for the treatment of rosacea; this strategy is associated with few adverse effects and has been proven safe for long-term use. Doxycycline relieves the inflammatory erythema that occurs after the treatment of PPR.11
Treatments for non-inflammatory erythema
The alpha-adrenergic receptor agonists present in dermal vessels (particularly in arterioles) cause vasoconstriction, which may be helpful in cases of persistent erythema. However, alpha-adrenergic receptor agonists have no effect on telangiectasias. Representative alpha-adrenergic receptor agonists include 0.33% brimonidine gel and 1% oxymetazoline cream, which were approved by the FDA for the treatment of persistent rosacea-associated erythema in 2014 and 2017, respectively. There are no significant differences on treatment effect between these two drugs.It is currently believed that these drugs only inhibit erythema temporarily.12
Common adverse events include increased erythema or flushing, itching, or burning sensation of the skin. Brimonidine is reportedly more likely to cause rebound than oxymetazoline.13 Several studies have reported that the combination of alpha-adrenergic receptor agonists and photoelectric therapy achieves better efficacy for ETR.14-15
Beta blockers have vasoconstrictive properties in the smooth muscle of dermal arterioles and do not act on capillaries, thereby alleviating the symptoms of flushing and erythema in patients with rosacea. In addition, beta blockers relieve anxiety and tachycardia, which also cause facial flushing. Representative beta blockers include carvedilol, propranolol, and nadolol. A systematic review recommended the use of oral nonselective beta blockers, especially carvedilol and propranolol, to treat rosacea-associated facial flushing and erythema.16 Carvedilol and propranolol may have additional antioxidant and anti-inflammatory effects, which are beneficial for the treatment of rosacea. Beta blockers are ideal for patients with rosacea with anxiety symptoms.17
The most common adverse effects of beta blockers include bradycardia, hypotension, bronchospasm. It is necessary to monitor the patient’s blood pressure and heart rate during treatment.
The hardener enters the target blood vessel and rapidly exfoliates the vascular endothelial cells, causing vascular fibrosis. The blood vessel then turns into a fibrous cord and is absorbed by the body. Ding and Zhao18 retrospectively analyzed the efficacy and safety of treatment with a vasodilator (polydocanol) in 12 patients with ETR. All patients were completely cured within 6 months after the first treatment. Only minor adverse effects occurred, such as redness and swelling.
Treatments for both types of erythema
Hydroxychloroquine exhibits certain anti-inflammatory, anti-immune, and anti-ultraviolet light damage properties. Hydroxychloroquine had the best effect on transient flushing or erythema, followed by papules and pustules, but there was no obvious effect on telangiectasia.19 No notable adverse reactions occurred during treatment. However, attention should be paid to the adverse effects of long-term use on the eyes, and regular fundus examination should be performed to rule out retinopathy. The 2016 China Consensus recommends the combination of oral hydroxychloroquine and sub-antibiotic doses of doxycycline as the first-line systemic treatment for persistent erythema that is unresponsive to topical drugs.7
Systemic or topical tranexamic acid is a conventional treatment for melasma. Tranexamic acid inhibits melanin formation, inhibits angiogenesis, and reduces erythema. A case report from Korea showed that the combined administration of oral minocycline, propranolol, and tranexamic acid treats rosacea, especially facial flushing, persistent erythema, and skin sensitivty.20 Furthermore, a clinical trial found that external tranexamic acid reduces facial erythema in patients with rosacea, probably due to its anti-angiogenic effect.21 Recent studies have reported that tranexamic acid significantly alleviates rosacea-associated erythema. One such study reported a marked reduction in the vascular network observed through a dermoscope.22 The inhibition of angiogenesis may be due to inhibition of the activity of fibrinolytic enzyme, which is a key substance in angiogenesis.23
Clinical and experimental studies have shown that artemisinin has anti-inflammatory and anti-angiogenic effects. Experiments with antimicrobial peptide LL-37-induced mice have shown that artemisinin may improve the symptoms of rosacea-associated erythema by inhibiting angiogenesis.24 However, the clinical efficacy and specific dosage still require further study.
Laser and other light-based therapies have been widely used to reduce telangiectasia and erythema, and the efficacy of pulsed dye laser (PDL), Nd: YAG laser, and intense pulsed light (IPL) therapies have shown a low to moderate level of certainty (based on high, moderate, low, and very low levels of certainty).25 The mechanism of action of laser therapy is selective photothermolysis, and the target chromophore is the hemoglobin pigment present in blood vessels. Photoelectric treatment also increases the local skin temperature, thereby killing mites, which may be the mechanism by which it reduces inflammatory erythema.
IPL (520–1200 nm)
IPL is used to treat many intractable rosacea symptoms, such as telangiectasias and erythema (mainly inflammatory erythema), but these symptoms may still not be completely relieved after multiple sessions.26 A half-face randomized controlled trial found that narrow spectrum IPL and subpurpura amounts of PDL result in no significant difference in the erythema index (EI) of patients with rosacea-associated erythema. However, due to the wide IPL pulse spectrum, it can act on different target color groups to treat different diseases and does not consume dyes, so narrow spectrum IPL is more highly recommended.27
PDL (585 nm or 595 nm)
PDL is used to treat erythema and telangiectasia. Its wavelength range of 585-595 nm makes it easily absorbed by oxygenated hemoglobin, thus reducing the risk of skin injury. An animal study showed that the PDL + hydroxymetazoline group had the highest rate of vascular occlusion and the longest maintenance time compared with other control groups14; the specific mechanisms of this treatment are still unclear, but may be related to the microvascular effect of hydroxymetazoline. A retrospective study found that PDL combined with topical 1% hydroxymetazoline cream is effective and safe in the treatment of rosacea and vascular dilatation.15 Another study showed that most patients (12/14) experienced continuous improvement in erythema symptoms and quality of life during a follow-up period of 21.64 ± 14.25 months.28
Nd: YAG laser (532 nm/1064 nm)
Nd: YAG laser therapy has good efficacy in the treatment of facial telangiectasia and is superior to IPL in the treatment of deeper vessels (5–6 mm under the skin) and telangiectasia larger than 1 mm. 1064 nm Nd: YAG laser and 595 nm PDL display a similar good efficacy in treating rosacea-associated erythema. Nd: YAG laser therapy is more suitable for patients with only telangiectasia, while PDL treatment is more suitable for those with erythema with mild telangiectasia.29
577-nm pro-yellow laser
A 577-nm pro-yellow laser, emitting 100% yellow-light energy, has an ideal wavelength for the treatment of vascular lesions with few adverse effects. Mohammed et al.30 treated 20 patients with PPR and 22 patients with facial telangiectasia with a 577-nm pro-yellow laser once a month. The energy was gradually increased from 12 J/cm2 to 16 J/cm2, and the pulse duration ranged from 20 ms to 26 ms. The effective rate in the PPR and facial telangiectasia groups was 90% and 100%, and a symptom improvement rate of over 75% occurred in 40% and 63.6% of patients, respectively. The treatment course required for an obvious effect was 3.1 ± 1.8 and 1.8 ± 0.85 sessions for PPR and facial telangiectasia, respectively. During the treatment process, only tolerable skin irritations and immediate erythema occurred.
Photodynamic therapy (PDT)
Photosensitizers undergo a photochemical reaction under the excitation of a specific wavelength of laser or light to produce reactive oxygen species, thereby inducing apo-ptosis and necrosis, causing vascular damage, and exerting anti-inflammatory, anti-tumor, and immune-regulating effects. One study showed that 5-aminolevulinic acid-PDT is an effective and safe treatment for ETR; however, the sample size was small, comprising only 17 patients. The 17 patients with rosacea-associated erythema underwent three sessions of aminolevulinic acid-PDT. The EI of the forehead and the EI of the nose were significantly decreased at 1 month after the final treatment compared with the pre-treatment values.31 Another study also showed that PDT is more effective in treating inflammatory erythema than non-inflammatory erythema.32
The most common adverse effects observed during PDT are desquamation, erythema, edema. Therefore, attention should be paid to skin moisturizing and sunscreen application after treatment.
Microfocused ultrasound (MFU-V)
One study reported that MFU-V can be used to treat ETR,33 possibly because it damages vascular obstruction and vascular walls. Large-scale clinical trials are still needed to evaluate the safety and effectiveness of MFU-V.
Botulinum toxin is a new drug used to treat rosacea. It is postulated that botulinum toxin inhibits the release of acetylcholine, substance P, and procalcitonin, which are associated with vasodilation and inflammation. Intradermal injection of botulinum toxin was effective in treating flushing and inflammatory erythema at 1 week after treatment, and the effect lasted for 3 months.34 Friedman et al.35 used a novel thermomechanical ablative system (Tixel) to increase the skin permeability immediately before ultrasound-guided botulinum toxin infiltration. The most obvious improvement in erythema was observed at 1 month after treatment. The erythema recurred slightly after 3 to 6 months but did not reach the baseline level. The only adverse effect was mild skin irritation, without muscle dysfunction or sagging skin.
The use of combination treatments to target specific features is necessary to achieve optimal outcomes in patients with erythema. Optoelectronic devices show good effects in the treatment of rosacea-associated erythema, especially in blood vessels. To help patients with rosacea achieve their treatment goals more completely and quickly, while maximizing remission periods and minimizing the burden of disease, optoelectronic devices can be combined with the abovementioned topical treatments and systemic medications.14-15,36
Multiple studies have proven that combination therapy is more effective and safer than monotherapy. PDL combined with topical oxymetazoline cream once daily is safe and effective in the treatment of rosacea-associated erythema and telangiectasia.15 Song et al.36 reported that the combination of PDL and topical 0.1% tacrolimus ointment is more effective than tacrolimus ointment alone for ETR.
Summary and outlook
There is still no unified worldwide diagnostic standard of rosacea. The diagnosis and classification of rosacea have evolved from a subtype approach to a phenotype approach, which enables the provision of specific treatment in accordance with the clinical manifestations of each patient, rather than being limited to four subtypes. Table 1 compares and summarizes the seven recent treatment guidelines for transient erythema, persistent erythema, and telangiectasia in patients with rosacea.
Table 1 -
of transient erythema, persistent erythema, and telangiectasia in patients with rosacea.
|2019 Global Rosacea Consensus (ROSCO)
||Topical a-adrenergics and oral beta blockers have been removed. These agents could be considered in certain situations.
||Local treatment: brimonidine, IPL, PDL,532nm KTP laser Systemic: None
||Local: electrodessication, IPL, laser
|2016 China Consensus
||Local: cold spray and cold compress preferred; brimonidine is alternative. Systemic: None.
||Local: azelaic acid, brimonidine, tacrolimus, and pimecrolimus are preferred Systemic: hydroxychloroquine+ subantimicrobial dosage of doxycycline is preferred; macrolides, carvedilol are alternatives
||Local: PDL, IPL, Nd: YAG laser, dual-wavelength laser
|2019 the USA Rosacea Society Expert Committee
||Local:(++), IPL; (+), Ivermectin, bromomonidine, hydroxymetazoline, KTP Systemic: (+), Carvedilol, Clonidine, propranolol
||Local: FDA-approved: bromomonidine and hydroxymetazoline. (++), IPL, PDL, KTP; Systemic: (+), Carvedilol, doxycycline (subantimicrobial), doxycycline, Minocycline, tetracycline
||Local: (++++), IPL, PDL, KTP; (+) Topical retinoids
|2017 Swiss guideline
||Local: 3*, brimonidine, IPL, PDL, Nd: YAG; 1*, azelaic acid, metronidazole, tacrolimus, pimecrolimus. Systemic therapy: 1a, carvedilol
||Local: 2*, IPL, PDL, Nd: YAG
|2016 Canada Clinical practice guideline
||Local: mild patients can use brimonidine, metronidazole, or azelaic acid; assess at 8–12 weeks, if ineffective, combine with vascular laser/IPL; moderate to severe patients can use brimonidine, metronidazole, or azelaic acid, assess at 8-12 weeks, if ineffective, combine with vascular laser/IPL Systemic: doxycycline
|2020 Brazil Consensus
||Soothing masks with chamomile, feverfew, green tea, etc; Intradermal botulinum toxin in large dilutions. Systemic: None.
||Local: Topical alpha-adrenergic agonists (brimonidine); Technologies (pulsed light or laser); Intradermal botulin in large dilutions. Systemic: None
||Electrocauterization or other technologies (laser or pulsed light)
|2020 Netherlands guideline
for temporary reduction of erythema: brimonidine gel q.d. when desired or “on occasion”
laser (PDL, Nd: YAG); IPL
laser (PDL, Nd: YAG); IPL Consider when associated inflammation is suspected: topical ivermectin, metronidazole, or azelaic acid
IPL: intense pulsed light; KTP: 532-nm Nd: YAG laser; PDL: pulsed dye laser.
The number of + signs indicates the committee’s expert opinion on the relative efficacy of the treatment, with four indicating the greatest degree of efficacy.
The term “consider” indicates a weak recommendation.
*Recommended level of treatment (from 1 to 3).
Recently, Chinese dermatologists proposed an improved version of the Chinese diagnostic criteria for rosacea.37 The standard divides the clinical manifestations of rosacea into two facial regions: the cheeks, the perioral area, and nose. The phenotypes are paroxysmal flushing and persistent erythema with periodic exacerbations. Erythema is important in the diagnosis of rosacea. Rosacea-associated erythema seriously affects quality of life and is difficult to treat.
The two forms of rosacea-associated erythema are inflammatory erythema and non-inflammatory erythema. All patients with rosacea-associated erythema should perform correct skin care. For inflammatory erythema, the first-line treatment is antibiotic preparations (such as ivermectin, metronidazole, and minocycline), and the second-line treatment includes oral antibiotic preparations (such as a sub-antibacterial dose of doxycycline) and photoelectric therapy when necessary (such as IPL and PDT). These methods effectively treat inflammatory erythema by exerting anti-inflammatory effects. However, the treatment of non-inflammatory erythema mainly relies on photoelectric therapy (such as PDL and Nd: YAG laser therapy), which can be combined with one or more local therapies (such as brimonidine and hydroxymetazoline) or systemic treatments (such as hydroxychloroquine and carvedilol) that act on blood vessels. IPL is more suitable for treating erythema with associated inflammation. IPL has a broad spectrum, and its energy cannot be concentrated on the blood vessels, so it has a weaker effect in treating erythema than PDL. Because Nd: YAG laser therapy has obvious advantages in treating thicker and deeper blood vessels, it is mainly used in patients with facial vasodilation. Botulinum toxin and vascular sclerotic treatments may be developed further in the future.
Recently, there has been a dramatic increase in the introduction of different therapies for rosacea. This review provides information that will enable clinicians to provide more comprehensive and individualized patient care based on the phenotypes present in each individual case. However, because of the limitations of current studies and no uniform standard for the dosage, duration of treatment and botulinum toxin injection method, large-scale controlled experiments are still needed to confirm the effectiveness and safety of some novel therapies.
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