Rosacea: Understanding the Essentials

Rosacea affects women more often than men and is particularly common in light-skinned people of Celtic origin. Its prevalence in the population ranges between less than 1% and 22%.

Rosacea has been classified by the National Rosacea Society Expert Committee into 4 subtypes:

1. erythematotelangiectatic
2. papulopustular
3. phymatose
4. ocular

According to this classification, the presence of at least one of the following main features in a central distribution on the face is diagnostic of rosacea: redness (transient erythema), non-transient erythema, papules and pustules, and telangiectasias. Secondary features, which may appear at the same time or independently, include burning or stinging sensation, plaque, dry appearance of the skin, edema, ocular manifestations, manifestation other than the face, and phymatous changes.

Given that rosacea often encompasses more than one subtype , that it can progress between subtypes, and that certain findings are pathognomonic (such as phymatous changes), the International Rosacea Consensus (ROSCO) panel recently proposed a different classification strategy, based on the phenotype and that more adequately covers the diversity of clinical presentations. However, this strategy has not yet been widely adopted.

The pathophysiology of rosacea remains uncertain. Genetic factors, deregulation of the innate and adaptive immune system, vascular and neuronal dysfunction, and microorganisms such as Demodex folliculorum appear to be involved . Triggers such as heat, stress, ultraviolet light, spicy foods, hot drinks, tobacco, and alcohol can exacerbate symptoms. Rosacea is associated with deterioration of the skin barrier, resulting in excess transepidermal water loss, making the skin dry, prone to flaking and peeling, and sensitive, with burning and stinging sensations.

? Strategies and evidence

? Driving

♦ General measures and skin care

Management of rosacea usually begins with educating the patient about the skin condition and potential exacerbating factors, helping them identify triggers and improve their coping mechanisms. Although data from randomized studies are lacking, clinical experience supports several general skin care measures.

A useful way to identify stimuli and triggers that may aggravate rosacea is to keep a daily diary. Given the deterioration of the skin’s barrier function, irritating cosmetic products should be avoided. Ultraviolet light is a well-known trigger; Therefore, daily use of sunscreen is recommended.

♦ Treatments of redness, erythema and telangiectasias

Data from randomized trials on interventions for transient erythema and flushing are poor. However, based on empirical evidence, when redness is bothersome, beta-blockers (e.g., nadolol, propranolol, and carvedilol) or α2-adrenergic agonists (e.g., clonidine) are often prescribed. Treatment with 0.5% brimonidine tartrate gel , a highly selective α2-adrenergic agonist with vasoconstrictor activity, was shown to reduce persistent erythema.

In a Cochrane meta-analysis that included 2 trials, a reduction in erythema was reported in 41% of patients in the brimonidine group compared with 20% of patients receiving vehicle. Within 30 minutes of applying brimonidine to the face, a visible improvement was observed that peaked between 3 and 6 hours after application, after which the effects progressively diminished.

Immediate side effects are erythema, pruritus, burning sensation, and redness; Rebound erythema may also occur with the use of brimonidine.

Likewise, treatment with 1% oxymetazoline hydrochloride cream, an α1-adrenergic agonist and an α2-adrenergic partial agonist, recently approved by the FDA for the treatment of persistent erythema associated with rosacea, is effective.

Although lasers and other light methods are widely used for the treatment of erythema and telangiectasias, they have been investigated mainly in observational studies.

♦ Treatments of inflammatory lesions

Azelaic acid, metronidazole and ivermectin are first-line medications for the treatment of rosacea

Treatments for inflammatory papules and pustular lesions depend on the severity of the inflammation. Azelaic acid, metronidazole and ivermectin , all applied topically, are first-line medications for the treatment of rosacea.

In 2 randomized controlled trials of 1,371 patients, treatment with topical ivermectin was associated with greater reductions in the number of inflammatory lesions over the course of 12 weeks compared with those treated with vehicle alone (66% vs. 39% in one trial). and 70% vs. 42% in the other).

The use of topical azelaic acid (15% gel, 15% foam or 20% cream, 2 times/day for 12 weeks) was evaluated in 5 randomized controlled trials, in a total of 1,245 patients, and they agreed to demonstrate a reduction in disease severity, as assessed by the patient and physician.

One of these trials, which evaluated the change in the number of baseline inflammatory lesions, showed a markedly greater reduction with azelaic acid than with vehicle (62% decrease vs. 47% decrease).

The efficacy of metronidazole 0.75% gel or cream, 2 times/day, or metronidazole 1% cream, 1-2 times/day, was investigated in 8 randomized controlled trials involving a total of 1,964 patients. , with durations that varied from 8 weeks to 6 months.

The reduction in the number of lesions was consistently greater in the metronidazole groups than in the placebo groups, with reductions ranging from 58% to 78% in the metronidazole groups and from 46% to 48% in the placebo groups.

A trial with 757 participants compared the effect of ivermectin 1%, once/day with that of metronidazole gel 0.75%, twice/day and measured the rates of maintenance of remission after 16 weeks of treatment.

Participants who had been assigned to the metronidazole group had a slightly higher rate of relapse (as defined by the recurrence of at least some inflammatory lesions) over a 36-week period than participants who received ivermectin (68% vs. 63%) and a shorter time to relapse (mean, 85 days vs. 115 days).

Other topical treatments that are sometimes prescribed include the combination of 10% sodium sulfacetamide and 5% sulfur in the form of a cream or lotion, 2 times/day; permethrin cream, 2 times/day and retinoids, 1 time/day; but data are limited to support the use of these treatments.

When first-line treatments are inadequate in mild cases or when rosacea has a more severe presentation, combining topical treatments and oral antibiotics is usually recommended , although supporting data are limited. The only oral treatment approved by the FDA and the European Medicines Agency for the inflammatory lesions associated with rosacea is modified-release doxycycline . 40 mg, 1 time/day.

This dose is considered to have an anti-inflammatory effect, but not an antimicrobial effect. In 2 randomized controlled trials of 537 patients, treatment with 40 mg doxycycline reduced the number of lesions significantly more than did placebo, with mean reductions of 46% and 61% in the doxycycline groups and mean reductions of 20 % and 29% in the placebo groups.

A randomized non-inferiority trial compared the administration of 40 mg of doxycycline with 100 mg of doxycycline and found that the 2 doses had similar efficacy, but substantially fewer adverse events (mainly gastrointestinal) in the lower dose group.

Tetracycline treatment has also been associated with significant reductions in the number of inflammatory lesions, but has more marked gastrointestinal side effects than doxycycline. Data are lacking to support the use of minocycline in rosacea, and in rare cases, it has been reported to cause serious side effects, such as skin and tissue hyperpigmentation, autoimmune hepatitis, and lupus erythematosus.

In cases where the use of tetracyclines is contraindicated or has previously caused unacceptable side effects, azithromycin, 250 to 500 mg, 2-3 times/week, and erythromycin, 250 to 500 mg, 1-2 times, can be used. /day and clarithromycin, 250 mg/1-2 days, although the use of each of these medications is supported mainly by observational studies.

For severe cases of inflammatory papules and pustules or for inflammatory papules and papules that do not respond to oral antibiotics or that recur after discontinuation of oral antibiotics, 2 randomized controlled studies tested the effectiveness of treatment with low doses of oral isotretinoin , 0.25 to 0.30 mg/kg body weight per/day for 12-16 weeks.

Isotretinoin should not be used in pregnant women or in women who may potentially become pregnant.

In one of these trials, isotretinoin was compared with doxycycline, at doses of 50 to 100 mg, and showed a slightly greater reduction in the number of lesions with isotretinoin than with doxycycline (89% vs. 83%). In the other trial, which compared isotretinoin with placebo, 57% of patients receiving isotretinoin showed a ≥90% reduction in the number of lesions compared with 10% of patients in the placebo group.

Isotretinoin should not be used in pregnant women or in women who may potentially become pregnant, as it is highly teratogenic. Prevention of pregnancy during isotretinoin treatment is essential; Routine pregnancy testing and effective birth control should be done.

♦ Treatments for fima

There is a lack of randomized controlled trials that evaluate interventions for fima. For fima with signs of inflammation, treatment with topical retinoids, oral doxycycline, oral tetracycline, or oral isotretinoin is recommended, based on clinical experience.

However, in cases where the fimas are not inflamed, more fibrotic and inactive, case series have shown marked improvement in their appearance and fewer symptoms after the use of ablative laser or surgical techniques, and the results are durable.

♦ Treatments for ocular rosacea

Ocular involvement occurs in up to three-quarters of rosacea patients but is often underdiagnosed and remains unstudied. Most guidelines advise hygiene of the eyelid twice a day with warm water and the application of artificial tears. A small randomized trial showed that cyclosporine drops improve quality of life, as measured by the Ocular Surface Disease Index, and increase tear production.

However, it should not be used when there is an active eye infection. Other therapeutic options for which there are limited data are topical metronidazole or fusidic acid applied to the eyelids. For patients with more severe ocular involvement, observational studies showed that 40 mg or 100 mg of oral doxycycline, modified release, can reduce symptoms.

If this does not occur, or if vision deterioration is proven, the patient should be referred to an ophthalmologist to rule out other diagnoses, monitor treatment, and prevent rare complications such as vision-threatening eye disease (e.g., keratitis).

♦ Treatments for pregnant or lactating women

Many interventions used for rosacea are not suitable for pregnant or breastfeeding women. Intense pulsed light therapy and laser are generally considered safe treatments, but they are often deferred until after pregnancy because they can be painful and distressing.

For inflammatory lesions, 0.75% metronidazole gel or 1% metronidazole cream, 15% azelaic acid gel, 15% foam or 20% cream, and the gel or solution can be used. of erythromycin 2%.

For ocular rosacea, fusidic acid gel is allowed. For oral treatment, only macrolide antibiotics such as erythromycin, clarithromycin and azithromycin have been recommended, but tetracyclines and isotretinoin are absolutely contraindicated.

♦  Maintenance treatment

Rosacea is a chronic disease, and although patients can have remissions, relapses are common. Therefore, they usually receive maintenance treatment, although data on remission rates derived from the effects of various therapies are limited. Topicals with metronidazole, azelaic acid and ivermectin have been shown to maintain remission after clearance of inflammatory lesions.

In a randomized trial of 88 participants in which metronidazole 0.75% was used, 2 times/day, it was compared with the effect of vehicle two applied 2 times/day, for 6 months; The relapse rate in the control group was almost double that of the metronidazole-treated group (42% vs. 23%).

In two extensions (40 weeks) of the trials (involving a total of 1,371 participants) in which 1% ivermectin cream was used, 1 time/day and compared with 15% azelaic acid gel, 2 times /day, it was found that adverse effects were rare but even less frequent with 1% ivermectin cream; The effectiveness of ivermectin increased over time.

In an open-label trial, brimonidine tartrate gel remained effective in reducing erythema over a 12-month period. For ocular rosacea, continuous hygiene of the eyelids and the use of artificial tears is recommended.

? Areas of uncertainty 

The pathophysiology of this condition is not completely understood. Associations have been observed with various chronic systemic conditions, such as cardiovascular diseases, metabolic disorders, autoimmune diseases, and Parkinson’s disease, but these associations require confirmation and further investigation.

There are few randomized controlled trials for some frequently used treatments, such as topical benzoyl peroxide (in monotherapy or in combination with topical antibiotics), topical retinoids, erythromycin, and oral azithromycin, while available studies have shown little or no benefit. of the treatment of ocular rosacea.

In clinical practice, various therapeutic options are often combined (e.g., topical, oral, and sometimes based on light therapies), but currently the evidence is insufficient to determine the efficacy and safety of these combinations.

Research is needed to promote maintenance treatments, as well as to establish the response time to the original treatment and the duration of response. Standardized and validated outcome measures 
would facilitate comparisons between trials and synthesis of data in a meta-analysis.

? Guides

The American Acne and Rosacea Society, the German Society of Dermatology, and most recently, the Canadian Dermatology Association have published guidelines for the treatment and management of rosacea. Furthermore, the international ROSCO panel recently published a consensus statement on the treatment of rosacea. The therapeutic strategy suggested in this article is in broad agreement with these guidelines.

? Conclusions and recommendations

The woman in the case presented here presents manifestations of rosacea (erythema, redness and inflammatory lesions). Rosacea encompasses a broad clinical spectrum, including erythema, telangiectasias, papules and inflammatory papules, phymatous changes, and ocular manifestations.

Like the woman described in the vignette, patients frequently present with more than one rosacea-associated phenotype. Treatment should be based on the presenting features and include combination treatments. Management should include patient education about rosacea and advice regarding routine skin care.

The author recommends that the patient keep a daily diary to help identify the triggers for her redness, and use non-irritating facial products and makeup that masks skin manifestations, in addition to a sunscreen with a protection factor ≥30.

Because the inflammatory lesions responded well to metronidazole gel 0.75% twice/day, it would be reasonable for the patient to restart the same regimen and continue it for at least 8 to 12 weeks. Other effective first-line treatments for inflammatory lesions are topical azelaic acid, 2 times/day or topical ivermectin, 1 time/day.

To treat the patient’s erythema, application of brimonidine tartrate gel or oxymetazoline cream in the morning could be considered. For maintenance treatment it is important to evaluate adherence, analyze the diary and the identified triggers.

If the response to topical agents alone is considered inadequate by the physician or the patient, or both, other therapeutic options such as systemic therapies (e.g., 40 mg or 100 mg of modified-release doxycycline) combined with agents may be discussed. topics. To reduce the risk of recurrence, it is recommended to continue therapy after rosacea remission.