Rosacea

Rosacea is a common condition characterized by symptoms of facial flushing and a spectrum of clinical signs, including erythema, telangiectasia, coarseness of skin, and an inflammatory papulopustular eruption resembling acne. ^{[1, 2]}

Rosacea is defined by persistent erythema of the central portion of the face lasting for at least 3 months. Supporting criteria include flushing, papules, pustules, and telangiectasias on the convex surfaces. Secondary characteristics are burning and stinging, edema, plaques, a dry appearance, ocular manifestations, and phymatous changes. The prevalence of these findings designates the subclassification of the presentation, as well as the therapeutic options. ^{[8, 9, 10]}

An expert committee assembled by the National Rosacea Society explicitly defined and classified rosacea into four different subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) on the basis of specific clinical signs and symptoms. Although didactically successful, the subtype designations were widely used individually and construed as distinct disorders, with the result that the frequent simultaneous occurrence of more than one subtype and the potential progression of one subtype to another were often ignored.

The diagnosis of rosacea is made clinically on the basis of the 2017 classification from the global rosacea consensus panel, ^[3]  which specified that one diagnostic or two major phenotypes are required for the diagnosis (see Criteria for Clinical Diagnosis).

Skin biopsy may be necessary to exclude other disease states that mimic the clinical presentation of rosacea. For example, the clinician must exclude polycythemia vera, connective-tissue diseases (eg, lupus erythematosus, dermatomyositis, mixed connective-tissue disease), photosensitivity, carcinoid syndrome, mastocytosis, long-term use of topical steroids, contact dermatitis, and photosensitivity before making the diagnosis of rosacea.

Because the details of the pathophysiology of rosacea have not yet been fully elucidated, therapeutic approaches empirically target the signs and symptoms of the disease. The classification systems aid clinicians in treatment by highlighting the preponderance of one or more of the clustering signs of presentation and thereby helping to determine which therapeutic approach to initiate.

Erythematotelangiectatic rosacea

Central facial flushing, often accompanied by burning or stinging, is the predominant sign in erythematotelangiectatic rosacea (ETR). The redness usually spares the periocular skin. These patients typically have skin with a fine texture that lacks the sebaceous quality characteristic of other subtypes. The erythematous areas of the face at times appear rough with scale, likely due to chronic low-grade dermatitis. Frequent triggers to flushing include acutely felt emotional stress, hot drinks, alcohol, spicy foods, exercise, cold or hot weather, and hot baths and showers. These patients also report that the burning or stinging is exacerbated when topical agents are applied.

Papulopustular rosacea

Papulopustular rosacea (PPR) is the classic presentation of rosacea. Patients are typically women of middle age who predominately present with a red central portion of their face that contains small erythematous papules surmounted by pinpoint pustules. They may have a history of flushing. Telangiectasias are likely to be present but may be difficult to distinguish from the erythematous background in which they exist.

Phymatous rosacea

Phymatous rosacea is defined as marked skin thickenings and irregular surface nodularities of the nose, the chin, the forehead, one or both ears, or the eyelids. Four distinct histologic variants can occur with rhinophyma (associated changes of the nose): glandular, fibrous, fibroangiomatous, and actinic. The mainstays of treatment are topical isotretinoin and surgical correction. This differs from treatment of other rosacea subtypes.

Ocular rosacea

Although ocular manifestations may precede cutaneous signs by years, they frequently develop concurrently with dermatologic manifestations. Ocular manifestations include blepharitis, conjunctivitis, inflammation of the lids and meibomian glands, interpalpebral conjunctival hyperemia, and conjunctival telangiectasias. Patients may describe eye stinging or burning, dryness, irritation with light, or foreign body sensation. Ocular rosacea, like phymatous rosacea, requires its own distinct therapeutic management. Therefore, dermatologists must ask their patients specifically about ocular symptoms and must perform a thorough physical examination to rule out this type of rosacea.

The etiology of rosacea is unknown. It is likely, however, that several factors play a role in its development, including vasculature, climatic exposures, dermal matrix degeneration, chemicals and ingested agents, pilosebaceous unit abnormalities, microbial organisms, ferritin expression, reactive oxygen species (ROS), increased neoangiogenesis, and dysfunction of antimicrobial peptides (AMPs). ^[11]  Furthermore, the distinct subtype of rosacea is likely determined by a patient's unique sensitivity to these triggers.

Vasculature

Increased blood flow to the blood vessels of the face and an increased number of blood vessels closer to the surface of the face are thought to be responsible for the redness and flushing associated with rosacea. Furthermore, vasodilatation, the normal response to hyperthermia, is thought to be more pronounced or exaggerated in individuals with rosacea.

Climatic exposures

Some studies have suggested that harsh climatic exposures (eg, from wind or ultraviolet [UV] light) damage cutaneous blood vessels and dermal connective tissue. This also includes exposure to solar irradiation, which may explain why rosacea predominately affects the facial convexities and has a tendency to flare in the spring. However, other studies have suggested the contrary, finding that most patients' symptoms do not worsen in the sunlight and do not flare with an acute exposure to UV light.

Dermal matrix degeneration

Rosacea involves associated damage to the endothelium and degeneration of the dermal matrix. However, it is not known whether (A) the initial damage is in the dermal matrix, leading to poor tissue support of cutaneous vessels and causing pooling of serum, inflammatory mediators, and metabolic waste; or (B) the initial abnormality exists in the cutaneous vasculature, leading to leaky vessels and delayed clearance of serum proteins, inflammatory mediators, and metabolic waste, thus resulting in matrix degeneration.

Chemicals and ingested agents

Spicy foods, alcohol, and hot beverages have traditionally been thought to trigger flushing in patients with rosacea. Most of the evidence, however, has not supported a central role for dietary factors in the pathogenesis. Moreover, certain medications (eg, amiodarone, topical steroids, nasal steroids, and high doses of vitamins B6 and B12) may cause flares for patients with rosacea. A rosacealike syndrome (including perioral dermatitis) can result from the indiscriminate use of potent corticosteroids on the face.  

Perivascular vs perifollicular inflammation

An inflammatory infiltrate may exist in a perivascular location, a perifollicular location, or both; however, studies to date have yielded conflicting answers to the question of which location predominates. There is a need for more studies designed to categorize subtypes of rosacea, in that the answer to this question varies according to the subclassification.

Microbial organisms

Demodex species (mites that normally inhabit human hair follicles) may play a role in the pathogenesis of rosacea. Some studies have suggested that Demodex prefers the skin regions that are affected in rosacea (eg, nose and cheeks). ^[12]  Some evidence indicates that an immune response of helper-inducer T-cell infiltrates occurs, surrounding the Demodex antigens in patients with rosacea. There is, however, conflicting evidence indicating that Demodex does not induce an inflammatory response in patients with rosacea. Moreover, Demodex is found in large numbers of healthy individuals without rosacea. Further study is required to determine whether Demodex truly is pathogenic.

Some studies have suggested that Helicobacter pylori may be associated with the etiology of rosacea. However, many of these studies were not controlled for confounding variables that influence H pylori prevalence (eg, sex, age, socioeconomic status, and medications). Furthermore, these studies did not have sufficient statistical power to account for the ubiquitous nature of H pylori infection.

Ferritin expression

Iron catalyzes the conversion of hydrogen peroxide to free radicals, which leads to tissue injury by damaging cellular membranes, proteins, and DNA. At the cellular level, unmetabolized iron is stored as ferritin. In a 2009 study, skin biopsy specimens from patients with rosacea were immunohistochemically analyzed, and the number of ferritin-positive cells was significantly higher in affected individuals than in control subjects. ^[13] Additionally, higher ferritin positivity correlated with more advanced subtypes of rosacea. Thus, increased release of free iron from proteolysis of ferritin can result in oxidative damage to the skin, which may contribute to the pathogenesis of rosacea.

Reactive oxygen species

Early in the inflammatory process, ROS are released by neutrophils, which are postulated to play a central role in the inflammation associated with rosacea. Free radicals (eg, superoxide anions and hydroxyl radicals), in addition to other reactive molecules (eg, molecular oxygen, singlet oxygen, and hydrogen peroxide), make up many of the ROS that lead to oxidative tissue damage. Several mechanisms have been adduced to explain how ROS result in skin inflammation, most notably the following ^{[14, 15]} :

• Deactivation of natural defenses caused by excessive oxidant stress from ROS
• Chemical and oxidative modification of proteins and lipids by ROS
• Alteration of the lipid balance, which, when normal, would suppress the creation of ROS
• Production of cytokines and other inflammatory mediators by keratinocytes, fibroblasts, and endothelial cells damaged by ROS
• Generation of ROS by cathelicidins, which are found in greater amounts in the facial skin of affected individuals

Neoangiogenesis and vascular endothelial growth factor (VEGF) overexpression

Studies performed using video capillaroscopy on ETR lesions showed increased neoangiogenesis and blood-vessel enlargement. Multiple immunohistochemistry studies showed increased vascular endothelial growth factor (VEGF) expression in vascular endothelium in lesional skin of rosacea patients as compared with nonlesional skin. Cuevas et al used topical dobesilate, an inhibitor of angiogenic growth factor, for the treatment of ETR and reported an improvement in erythema and telangiectasia after 2 weeks. ^[16]

Antimicrobial peptides

AMPs are low-molecular-weight proteins that are a part of the innate immune response and have demonstrated broad-spectrum antimicrobial activity against bacteria, viruses, and fungi. They are rapidly released upon injury or infection of the skin and have been implicated in the pathogenesis of many inflammatory skin diseases. Two of the best-known AMP types are the cathelicidins and the β-defensins; the former are known to be expressed at abnormally high levels in patients with rosacea.

Specifically, the LL-37 peptide form of cathelicidin, in addition to proteolytically processed forms of LL-37, has been found in significantly higher amounts in rosacea patients than in healthy individuals. LL-37 is expressed by polymorphonuclear leukocytes and lymphocytes. It interacts with endothelial cells and stimulates angiogenesis both in vitro and in vivo; it also modulates the expression of VEGF. ^[11]  Injection of LL-37 and these peptides derived from LL-37 into mice was found to induce inflammation, erythema, and telangiectasia; accordingly, researchers hypothesized that an excess of cathelicidins coupled with abnormal processing caused disease. ^[17]

Accurate incidence data for rosacea are not available; however, rosacea is known to be a common skin condition that disproportionately affects persons of fair-skinned European and Celtic origin. In the United States, it has been estimated that more than 16 million people are affected by rosacea; worldwide, the prevalence is estimated to exceed 5% overall and may be as high as 18% in some areas. ^[18] A study in Sweden revealed an incidence of one case in 10 middle-class workers. The caseating granulomatous variant (acne agminata) may occur more commonly in people of Asian or African origin.

Rosacea also occurs in people with dark skin but is less frequently diagnosed in such populations. It is unknown whether factors such as masking of facial redness by abundant skin pigment, protective effects of melanin against UV light, and genetic predisposition to rosacea contribute to the lower rate of diagnosis in people with skin color.

Both males and females are affected by rosacea; however, females appear to be affected with slightly greater frequency. ^[19] different lesions appear to have some age- or sex-related predilections. ^[18] In younger patients, the first signs are more likely to be flushing and erythema, whereas in older patients, the first lesions are more likely to be telangiectasias. Phymatous rosacea is predominantly found in males. ^[19]

A spectrum of clinical features is seen, and progression may be stepwise. The condition ranges from minor cosmetic disability to severe disfiguring disease. In most patients who receive treatment, a stable state is reached with variable residual symptoms. In some patients, the disease takes a chronic relapsing or progressive course.

Patients should be advised to avoid known exacerbating factors, such as hot or cold temperatures, wind, hot drinks, caffeine, exercise, spicy food, alcohol, strong emotions, topical products that irritate the skin and decrease the barrier, and medications that cause flushing. Patients should be encouraged to use a noncomedogenic high-factor sunscreen when exposed to sunlight and wind.