The etiology and pathophysiology of rosacea are not completely understood, but there is evidence to support a genetic predisposition. This includes the increased prevalence of rosacea in some northern European populations and the association of rosacea with autoimmune disorders.¹⁹ Gene array and polymerase chain reaction analyses indicate a defined gene profile for each of the different rosacea subtypes.¹²,²⁰ Proposed factors that may be contributory to the development of rosacea include abnormal vascular reactivity, dysregulation of the innate immune system, increased susceptibility of sensory nerves to temperature changes or spicy foods, ethanol, exercise, UV radiation, Demodex overgrowth on the face or small intestinal bacterial overgrowth, and pilosebaceous unit abnormalities.⁴,¹³,²¹,²²,²³,²⁴

Rosacea shows great variation in clinical manifestations suggesting a possible wide range of pathophysiological mechanisms.²⁵ The major elements appear to be an augmentation of immune reaction and response, and neurovascular
dysregulation.²⁵,²⁶ There is an upregulation of genes involved in vasoregulation and neurogenic inflammation in all subtypes of the disease.²⁷ The causes of transient flushing are poorly understood, but some evidence suggests it is associated with the release of antimicrobial peptides and proteases,²⁸ neuropeptides,¹³ or transient receptor potential ion channels²⁹ in the induction of erythema and vasodilation. The inflammatory infiltrate present in all four subtypes is not well characterized, but in early-onset rosacea, a lymphomonocytic infiltrate consisting primarily of CD3+ T cells, with CD20+ B cells, mast cells, and dendritic cells has been described.²⁵,²⁷,³⁰

Environmental factors that are known to exacerbate the disease lead to the activation of proinflammatory products and innate immune responses.²⁰,²¹ Cathelicidin, which has both vasoactive and proinflammatory actions, is elevated in the skin of patients with rosacea and has been implicated in its pathogenesis.²¹,²⁸,³¹

In patients with ocular rosacea, the inflammatory basis of the disease is supported by elevated concentrations of interleukin-1a and 1b, tumor necrosis factor-alpha, and a greater activity of metalloproteinase-9 and collagenase-2 in tear fluids.³²,³³,³⁴,³⁵ Overexpression of toll-like receptor 2 on keratinocytes may explain enhanced inflammatory responses to environmental stimuli and may be a factor in the pathogenesis of rosacea.³⁶ The inflammatory markers ICAM 1 and HLA-DR have also been observed to be overexpressed in conjunctival epithelial cells.³⁷

The symptoms of rosacea show episodes of exacerbations and remissions, but over time the disease usually progresses. While certain trigger factors such as sun exposure, extreme temperatures, alcohol, spicy foods, exercise, and emotional stress can worsen the symptoms, others, like smoking, appear to significantly reduce the risk of developing rosacea.³ Facial rosacea may present with little or no simultaneous eyelid involvement⁷ (Figure 109.1) More often, facial lesions include acne, sebaceous thickening with edematous papules and pustules, and thickening of the nose as rhinophymia (Figure 109.2). The eyelid inflammatory reaction results in meibomian gland dysfunction, chronic scarring of the gland orifices, and eyelid margin telangiectasias. This leads to tear film instability, epiphora, photophobia, keratitis, and blurred vision.³⁸,³⁹ Other common findings include blepharitis and collarettes around the eyelashes. Patients often experience recurrent hordeola and chalazia (Figure 109.3).⁷,¹⁷ Dry eye is a major finding in up to two-thirds of patients with ocular rosacea,³⁷,⁴⁰ and pinguecula, chronic cicatricial conjunctivitis, and fibrosis have also been reported.⁴¹,⁴²,⁴³

Corneal manifestations may be seen in up to 33% of patients.³⁸,⁴⁴ These can include superficial punctate keratitis on the lower third of the cornea and peripheral neovascularization with subepithelial infiltrates and can proceed to stromal ulceration, and even corneal perforation.⁴⁵,⁴⁶ Iritis, episcleritis, and scleritis are other potential ocular findings,⁷,⁴⁷ and a case of spontaneous scleral perforation has been described.⁴⁸

Systemic lupus erythematosus is a skin condition that can mimic rosacea. This is a chronic inflammatory disease that has protean clinical manifestations, which include malar erythema in approximately 50% of patients. The erythema may last for hours to days and often recurs, especially with sun exposure.⁴⁹,⁵⁰ Dermatomyositis is an inflammatory myopathy characterized by varying degrees of muscle weakness and skin erythema, but some patients lack muscular involvement and initially present only with skin manifestations. Macular violaceous erythema occurs most frequently in the seborrheic area of the face⁵¹ that might be

confused with the erythema seen in rosacea. Polymorphous light eruption is a common idiopathic photodermatosis with a higher prevalence in fair-skinned individuals,⁵² characterized by erythematous papules, papulovesicles, and plaques on exposed skin surfaces following sun exposure.⁵³ Seborrheic dermatitis is a chronic skin disease characterized by a relapsing erythematous rash with well-demarcated patches, papules, or plaques seen most often on sebum-rich areas such as the face and scalp. Acne vulgaris is characterized by noninflammatory comedones and inflammatory papules, pustules, and nodules. It typically affects areas of skin with a high density of sebaceous glands such as the face, upper chest, and back.⁵⁴ Other rare conditions that have been misdiagnosed as rosacea include carcinoid syndrome with flushing of the face, neck, and upper trunk⁵⁵ and cutaneous lymphoma that can present with violaceous papules, plaques, and nodules on the face.⁵⁶