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Rosacea: Pathogenesis, clinical features, and diagnosis

Pathogenesis, clinical features, and diagnosis
Pathogenesis, clinical features, and diagnosis
Rosacea: Pathogenesis, clinical features, and diagnosis
Author
Mark V Dahl, MD
Section Editor
Robert P Dellavalle, MD, PhD, MSPH
Deputy Editor
Abena O Ofori, MD

INTRODUCTION — Rosacea is a common, chronic skin disorder that presents with a variety of clinical manifestations primarily localized on the central face [1,2] . The disorder is divided into four main subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea.

Persistent centrofacial redness is a characteristic feature of the erythematotelangiectatic form of rosacea, while papulopustular disease presents with acne-like inflammatory papules and pustules in a similar distribution. The less common phymatous form of rosacea may demonstrate marked skin thickening and distortion of facial contours. Ocular rosacea, which often presents with eye redness, pruritus, or irritation, can occur in the presence or absence of cutaneous disease.

The pathogenesis, clinical manifestations, and diagnosis of rosacea will be reviewed here. The treatment of rosacea is discussed separately. (See "Management of rosacea".)

EPIDEMIOLOGY — Rosacea is a common disorder that is most frequently observed in fair-skinned individuals (skin phototypes I and II) (table 1). People of Celtic and Northern European origin appear to have the greatest risk for this disorder [3,4] . The prevalence of rosacea is difficult to assess due to its variable clinical manifestations and the wide variety of skin disorders that exhibit similar clinical features (see 'Differential diagnosis' below). Estimates of the prevalence of rosacea in fair-skinned populations range from 1 to 10 percent [3,5,6] .

Rosacea occurs in people with darker skin complexions, but is less frequently diagnosed in such populations (picture 1A-B) [7-12] . It is unknown whether factors such as masking of facial redness by abundant skin pigment, protective effects of melanin against ultraviolet radiation (an exacerbating factor for rosacea), or genetic differences in susceptibility to rosacea contribute to the lower rate of diagnosis in people with dark skin.

Adults over the age of 30 are the primary age group affected by rosacea, and the disorder occurs more frequently in women than in men [3,13] . Phymatous rosacea is an exception; the vast majority of affected patients are adult males.

Rarely, rosacea occurs in children. Children may exhibit all subtypes except the phymatous form of the disease, and symptoms may persist into adulthood [14-16] .

PATHOGENESIS — The pathways that lead to the development of rosacea are not well understood [17,18] . Proposed contributing factors include abnormalities in innate immunity, inflammatory reactions to cutaneous microorganisms, ultraviolet damage, and vascular dysfunction.

Immune dysfunction — The innate immune system plays a key role in the cutaneous immune response to microorganisms and to insults such as ultraviolet radiation and physical or chemical trauma [19] . Dysfunction of the innate immune system may contribute to the development of chronic inflammation and vascular abnormalities in rosacea.

The process through which aberrations of the innate immune system may contribute to rosacea may involve the production of abnormal cathelicidin peptides that have vasoactive and inflammatory properties [19] . Increased levels of abnormal cathelicidin and kallikrein 5 (a processing enzyme for cathelicidin that is also known as stratum corneum tryptic enzyme) have been detected in skin from patients with rosacea [20] .

The subsequent discovery that toll-like receptor 2, a component of the innate immune system that interacts with environmental stimuli, can stimulate release of kallikrein 5 from epidermal keratinocytes offers a potential explanation for a link between environmental insults and cathelicidin-mediated abnormalities in rosacea [21] . Moreover, a study in which the injection of mouse skin with cathelicidin peptides from patients with rosacea led to inflammation and vascular dilatation provides additional evidence in support of cathelicidin as a pathogenic factor [20] .

Microorganisms — Stimulation of inflammatory reactions by microbes in or on the skin has been proposed as an inciting factor for cutaneous inflammation in rosacea.

Demodex — Demodex folliculorum is a saprophytic mite that resides in sebaceous follicles. Although Demodex mites can be found on normal skin in almost all adults, increased density of Demodex mites in patients with rosacea has been reported in multiple studies [22-25] . In a meta-analysis of case-control studies, a statistically significant association betweenDemodex infestation and rosacea was detected, with the degree of infestation being more important than the rate of infestation [22] . The role ofDemodex mites as an inciting factor for rosacea remains uncertain.

Bacillus olenorium — The knowledge that papulopustular rosacea improves with antibiotic therapy led to an in vitro study investigating Bacillus olenorius, a bacterium that was cultured from a single Demodex mite, as a potential cause of inflammation in rosacea [26] . The study found that antigens fromB. olenorius stimulated proliferation of peripheral blood mononuclear cells from 16 out of 22 patients with rosacea (73 percent) versus only 5 out of 17 patients without rosacea (29 percent). Additional studies are necessary to determine whether B. olenorius is a common colonizer of Demodex mites and whether the organism is involved in the pathogenesis of rosacea.

Helicobacter pylori — The relationship between gastrointestinal Helicobacter pylori infection and rosacea is uncertain due to conflicting data on the prevalence of H. pylori infection among patients with rosacea. While some studies have reported increased rates of H. pylori infection in patients with rosacea, others have not found an association between the disorders [27] . In addition, studies conflict on whether treatment ofH. pylori improves rosacea. It is conceivable that antibiotic therapy to eradicate the infection could simultaneously ameliorate rosacea through unrelated mechanisms.

Proposed pathogenic mechanisms for H. pylori infection in rosacea include the promotion of inflammation due to reactive oxygen species produced by H. pylori and bacterium-induced cytokine production by gastric epithelial cells [17] .

Other — Staphylococcus epidermidis [28,29] ,Chlamydia pneumoniae [30] , and small intestine bacteria [31]  have been linked to rosacea in a few studies. Additional investigation is necessary to determine whether any of these organisms have a significant impact on the development of rosacea.

Ultraviolet radiation — Sun exposure is often cited as an exacerbating factor for rosacea, based upon the distribution of lesions on chronically sun-exposed skin, the detection of signs of solar elastosis on skin biopsy specimens, and the preferential appearance of the disorder in fair-skinned individuals.

Several theories on the mechanisms through which sun exposure could promote rosacea have been proposed. Ultraviolet B radiation has been shown to induce cutaneous angiogenesis in mice and can stimulate the secretion of vascular endothelial growth factor (VEGF)-2 and fibroblast growth factor (FGF)-2 from keratinocytes [32-34] . Ultraviolet radiation may also stimulate production of damaging reactive oxygen species and may incite activation of the innate immune system [19] .

However, study data confirming an association between all subtypes of rosacea and ultraviolet radiation are lacking [35] . Fewer than one-third of patients with rosacea report exacerbations of symptoms with sunlight [35] , and a retrospective study in Korea of 168 patients with rosacea found that although high daily sun exposure correlated with increased severity of erythematotelangiectatic disease, it did not appear to have a significant effect on papulopustular, phymatous, or ocular rosacea [10] . In addition, a study of 1000 adults in Ireland found no difference in the prevalence of papulopustular rosacea in subjects with high sun exposure versus those with lower sun exposure [6] . Further studies are necessary to explore the impact of ultraviolet radiation on the various subtypes of rosacea.

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As noted above, extremes of temperature can be an exacerbating factor for rosacea. Thus, aside from ultraviolet light, infrared radiation (radiant heat) from sun exposure could contribute to exacerbations of rosacea.

Vascular hyperreactivity — Frequent and prolonged flushing is a common feature in rosacea and triggers of flushing (eg, spicy foods, alcohol, and extremes of temperature) have been anecdotally associated with worsening disease (see 'Exacerbating factors' below). In addition, increased blood flow has been detected in the skin of some patients [12,36] .

These observations suggest a role for vascular hyperreactivity in the pathogenesis of this disorder [19] . Dysregulation of thermal mechanisms has also been proposed as a contributing factor to flushing in rosacea [35] .

Genetics — Individuals with a family history of rosacea may be more likely to develop the disorder [13] . However, specific genetic factors associated with increased risk for rosacea have not been identified. Further studies are necessary to explore the impact of family history and genetic background on risk for rosacea.

CLASSIFICATION AND CLINICAL FEATURES — There are four main subtypes of rosacea: erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea [37] . Patients may present with features of one or multiple subtypes.

Although lesions of erythematotelangiectatic and papulopustular rosacea classically involve the central face, involvement of other sites such as the ears, lateral face, neck, scalp, and chest occasionally occurs [35] .

Erythematotelangiectatic rosacea — Persistent facial erythema and recurrent episodes of facial flushing are characteristic features of erythematotelangiectatic rosacea. A summary of common features of the erythematotelangiectatic subtype of rosacea is below:

  • Persistent centrofacial erythema – Patients exhibit chronic redness of the nose and medial cheeks (picture 2A-B).
  • Flushing – This can be wet (accompanied by sweating) or dry, and may be associated with subtle transient facial swelling. Examples of triggers for flushing are provided (see 'Exacerbating factors' below).
  • Telangiectasias – Telangiectasias are visible enlarged cutaneous blood vessels (picture 3). In rosacea, telangiectasias are predominantly located on the central face, especially on the cheeks.
  • Roughness and scaling – A dry quality to the skin is often present.
  • Skin sensitivity – Stinging or burning sensations in affected areas are common in patients with rosacea. Skin care products may irritate the skin and aggravate symptoms.
  • Erythema congestivum – After an exacerbation of facial redness, the appearance of patients with rosacea returns to baseline more slowly than individuals without rosacea.

Papulopustular rosacea — Papulopustular rosacea is marked by the presence of papules and pustules primarily localized to the central face (picture 1C, 1A, 1D, 1B). Lesions may be mistaken for inflammatory acne vulgaris. Unlike acne vulgaris, comedones do not occur in rosacea and inflammation may extend outward well beyond the follicular unit to form plaques. As an example, in occasional patients the whole nose may be tender, swollen, and red.

Phymatous rosacea — Phymatous rosacea exhibits tissue hypertrophy manifesting as thickened skin with irregular contours (picture 2). Involvement most commonly occurs on the nose (rhinophyma), but may also be seen in other sites such as the chin (gnathophyma), forehead (glabellophyma), and cheeks (malarphyma). Patients who develop this subtype of rosacea often have prominent sebaceous hyperplasia and very oily skin. The vast majority of patients with phymatous rosacea are adult men.

Ocular rosacea — Ocular involvement occurs in more than 50 percent of patients with rosacea [38]  Ocular rosacea may precede (20 percent), follow (50 percent), or occur concurrently with cutaneous disease [37] . Both children and adults may be affected [14,39] .

Clinical manifestations of ocular rosacea include conjunctival hyperemia, anterior blepharitis, keratitis, lid margin telangiectases, abnormal tearing, cicatricial conjunctivitis, and chalazion or hordeolum (stye) formation. Potential symptoms include dry eye, foreign body sensations, stinging, burning, pruritus, photosensitivity, and blurry vision.

Granulomatous rosacea — The relationship of granulomatous rosacea to other forms of rosacea has been debated, but in 2002, a committee of experts recognized this disorder as a variant of rosacea [37] . Granulomatous rosacea presents with yellow-brown or monotonous pink papules that are usually distributed on the cheeks and perioral skin; background facial erythema and flushing are often absent. A granulomatous infiltrate is characteristically present on biopsy [35] .

Pediatric rosacea — Rarely, children develop erythematotelangiectatic, papulopustular, or ocular rosacea. The clinical features of pediatric rosacea resemble those of rosacea in adults [14-16,39,40] . Phymatous rosacea does not occur in children.

EXACERBATING FACTORS — Multiple factors have been anecdotally associated with exacerbations of cutaneous signs and symptoms of rosacea, including:

  • Exposure to extremes of temperature
  • Sun exposure
  • Hot beverages
  • Spicy foods
  • Alcohol
  • Exercise
  • Irritation from topical products
  • Psychological feelings, especially anger, rage, and embarrassment
  • Certain drugs such as nicotinic acid and vasodilators

In the past, phymatous rosacea was perceived by the lay public to be a consequence of heavy alcohol consumption. However, definitive evidence in support of an association between alcohol and phymatous rosacea is lacking [35] .

DIAGNOSIS — Clinical assessment of the patient is usually sufficient for the diagnosis of erythematotelangiectatic, papulopustular, and phymatous rosacea. The histopathologic findings in these subtypes are nonspecific, and skin biopsies are rarely indicated. When the diagnosis is uncertain, biopsies may be performed to rule out other disorders or to provide support for a diagnosis of granulomatous rosacea. No serologic studies are useful for diagnosis.

Histopathology — Specimens from erythematous facial skin in erythematotelangiectatic rosacea usually show dilation of superficial blood vessels and a low grade perivascular lymphohistiocytic inflammatory infiltrate with occasional plasma cells. Solar elastosis is often present.

Histopathologic examination of papular lesions usually reveals prominent perivascular and perifollicular inflammatory infiltrates in the superficial and mid-dermis composed of lymphocytes, neutrophils, and plasma cells. Superficial accumulations of neutrophils are present in pustular lesions. In contrast to acne vulgaris, inflammation often extends well beyond the follicle [41] .Demodex mites are often detected in follicular orifices.

The histopathologic findings in phymatous rosacea include sebaceous gland hyperplasia, follicular plugging, telangiectasias, pronounced dermal thickening and fibrosis, and large amounts of dermal mucin. Increased numbers of Factor XIIIa positive cells may be present in the dermis [42,43] .

Granulomatous rosacea is characterized by the presence of epithelioid granulomas adjacent to hair follicles. Caseation is present in approximately 10 percent of cases [44] .

Referral to ophthalmology — Patients who have ocular symptoms or who are found to have visible signs suggestive of ocular rosacea should be referred to ophthalmology for further evaluation.

DIFFERENTIAL DIAGNOSIS — A variety of skin conditions may present with clinical features that resemble erythematotelangiectatic, papulopustular, or granulomatous rosacea.

Erythematotelangiectatic rosacea — The following conditions share features with erythematotelangiectatic rosacea:

  • Ruddy complexion – Some fair-skinned patients, particularly those of Celtic origin, may have a naturally ruddy complexion to the skin. In contrast to the ruddy complexion, redness in rosacea primarily involves the central face.
  • Sun-damaged skin – Telangiectasia may occur as a manifestation of sun-damaged skin. Dyspigmentation and skin wrinkling are often also present. In contrast to rosacea, which primarily affects the central face, sun damage is often most evident on the lateral face and neck. The presence of other characteristics of rosacea, such as persistent facial erythema and frequent flushing, also support a diagnosis of rosacea.
  • Seborrheic dermatitis – Macular erythema and scale involving the perinasal area is a common finding in seborrheic dermatitis (picture 3). A greasy quality to the scale and involvement of other sites such as the scalp, retroauricular skin, and brow suggest this diagnosis. (See "Seborrheic dermatitis in adolescents and adults".)
  • Acute cutaneous lupus erythematosus –  The centrofacial redness in rosacea may be confused with malar erythema of systemic lupus erythematosus, particularly in patients who lack papulopustular lesions (picture 4A-B). In lupus, the color of the skin has a violaceous quality and may show a more abrupt cutoff, especially at its most lateral margins (resembling a butterfly wing).

    Serologic testing for antinuclear antibodies in all patients with classic features of erythematotelangiectatic rosacea is not indicated. Patients should be clinically assessed for signs or symptoms of systemic lupus; the need for laboratory work-up should be based upon the presence of mucocutaneous or systemic findings suggestive of this disorder. Skin biopsies of acute cutaneous lupus erythematosus usually demonstrate interface dermatitis, a feature that does not occur in rosacea. (See "Mucocutaneous manifestations of systemic lupus erythematosus", section on 'Butterfly rash'.)

  • Dermatomyositis – Dermatomyositis is an idiopathic inflammatory disorder that can affect skin and muscle tissue. Violaceous erythema involving the periorbital skin and central face can occur. The dusky, violaceous color of the facial eruption differs from the bright erythema that is typically seen in rosacea (picture 5). Examination for muscle weakness and other cutaneous signs of dermatomyositis is useful for diagnosis. Like acute cutaneous lupus erythematosus, skin biopsies reveal features of an interface dermatitis. (See "Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis".)
  • Other flushing disorders – In addition to rosacea, facial flushing may occur in a wide variety of disorders. Examples include medication reactions, menopausal hot-flashes, neurologic disorders, carcinoid syndrome, mastocytosis, pheochromocytoma, medullary thyroid carcinoma, and serotonin syndrome. The possibility of such disorders should be considered in patients who present with flushing. (See "Flushing".)

Papulopustular rosacea — The following disorders share features with papulopustular rosacea:

  • Acne vulgaris – Acne vulgaris is the most common skin disorder in the differential diagnosis of papulopustular rosacea. Individual inflammatory lesions of the two disorders may appear clinically identical. A key distinguishing feature between acne vulgaris and rosacea is the absence of comedones in rosacea (picture 6). A prominent centrofacial distribution also suggests a diagnosis of rosacea. Acne vulgaris and rosacea coexist in some patients. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".)
  • Topical steroid-induced acneiform eruptions – Topical corticosteroid use can result in the appearance of monomorphic inflammatory papules on facial skin. The patient history is valuable for diagnosis. (See "General principles of dermatologic therapy and topical corticosteroid use", section on 'Cutaneous'.)
  • Perioral dermatitis – Perioral dermatitis presents with numerous small papules with fine scale in the perioral area (picture 7A-B). Sparing of the skin adjacent to the vermillion border of the lip is characteristic. Lesions may also occur in periorbital and perinasal distributions. In patients who have erroneously attempted to treat the eruption with topical corticosteroids, acneiform eruptions may also be present.
  • Keratosis pilaris rubra faceii – Persistent, rough, 1 to 2 mm follicularly-based papules on the face can occur as a manifestation of keratosis pilaris in children, adolescents, and young adults (picture 8). The condition presents with a rough, red, symmetrical, triangular patch of skin on each cheek that lacks papules or pustules. Typical keratosis pilaris also may be present on the backs of the arms and fronts of the thighs (picture 9A-B).
  • Demodicosis (Demodex folliculitis) – Demodicosis can present with numerous inflammatory papules on the face and is difficult to distinguish from papulopustular rosacea on clinical examination [45] . Potassium hydroxide (KOH) preparation or skin punch biopsy may demonstrate numerousDemodex mites crowding the follicular orifice. However, Demodex mites are also commonly detected in rosacea and in normal skin. Immunocompromised patients are at increased risk for this disorder. (See "Dermatologic procedures", section on 'Potassium hydroxide prep'.)

Granulomatous rosacea — The features of granulomatous rosacea overlap with other disorders described in the literature that present with numerous, small, monomorphic facial papules and granulomatous infiltrates on biopsy. In adults, lupus miliaris disseminatus faciei, which presents with multiple red-brown 2 to 5 mm papules on the face and caseating granulomas on biopsy, has been reported [46-48] . In addition, granulomatous facial dermatoses identified as childhood granulomatous periorificial dermatitis [49-51]  and facial Afro-Caribbean childhood eruption [52,53]  have been described in children. The status of these disorders as independent entities or forms of rosacea is unclear.

PYODERMA FACIALE (ROSACEA FULMINANS) — The relationship of pyoderma faciale (also known as rosacea fulminans or rosacea conglobata) to rosacea also is uncertain [37] . Patients present with intensely inflammatory, purulent facial plaques and nodules with draining sinuses on a background of erythema (picture 10) [54,55] . A history of rosacea may or may not be present. Young women are most commonly affected.

SUMMARY AND RECOMMENDATIONS

  • Rosacea is a common skin disorder that may occur in adults of all ethnic backgrounds, but is most commonly diagnosed in individuals with fair skin. Rarely, rosacea occurs in children. (See 'Epidemiology' above.)
  • The pathogenesis of rosacea is poorly understood. Factors such as abnormalities in the innate immune system, inflammatory reactions to cutaneous microorganisms, ultraviolet radiation exposure, and vascular hyperreactivity have been identified as potential contributing factors. (See 'Pathogenesis' above.)
  • Rosacea is divided into four main subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea. Granulomatous rosacea may be a variant of rosacea. (See 'Classification and clinical features' above.)
  • Persistent facial redness, recurrent facial flushing, telangiectasias, and skin dryness and sensitivity are common features of erythematotelangiectatic rosacea. Lesions of papulopustular rosacea closely resemble inflammatory acne. Features of both subtypes are primarily localized on the central face. (See 'Classification and clinical features' above.)
  • In most patients, clinical assessment is sufficient for diagnosing rosacea and excluding other disorders that may resemble rosacea. Skin biopsies are rarely indicated, but can be useful in cases in which another disorder with specific histopathologic findings is suspected or for supporting a diagnosis of granulomatous rosacea. (See 'Diagnosis' above and 'Differential diagnosis' above.)
  • Ocular rosacea may present independently or in association with cutaneous subtypes of rosacea. Patients may exhibit features such as conjunctival hyperemia, blepharitis, and ocular irritation. Patients with signs or symptoms of ocular rosacea should be referred to an ophthalmologist for further evaluation. (See 'Ocular rosacea' above and 'Referral to ophthalmology' above.)

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