Manual of Dermatologic Therapeutics
7th Edition
© 2007 Lippincott Williams & Wilkins
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28
Rosacea and Perioral (Periorificial) Dermatitis
Peter C. Schalock
I. Definition and Pathophysiology
  • Rosacea is a chronic disorder of unknown etiology that affects the central face and neck. At least 13 million people are affected by this noncurable disorder. It is characterized by two clinical components: a vascular change consisting of intermittent or persistent erythema and flushing and an acneiform eruption with papules, pustules, cysts, and sebaceous hyperplasia. There is no correlation between the sebum excretion rate and the severity of rosacea. Lesional blood flow as measured by laser Doppler is three to four times that of controls. Onset is most often between the ages of 30 and 50; pediatric cases have also been reported. Although women are affected three times as frequently as men, the disease may become more severe in men. Rosacea is much more common in light-skinned, fair-complexioned individuals but may also occur in darker skin types. It is estimated that 10% of individuals in Sweden have rosacea.
    There is speculation that a defect in the trigeminal afferent nerve pathway contributes to a predisposition to facial flushing. Over time, after repeated bouts of flushing, the vessels become ectatic and there is permanent vasodilatation. Hot liquids are thought to promote erythema and flushing when they heat up the tissues of the oral mucosa, leading to a countercurrent heat exchange with the carotid artery. A further signal from the carotid body is then relayed to the hypothalamus (the body’s thermostat), which signals the body to dissipate heat through flushing and vasodilatation because of the perceived increase in core body temperature.
    The diagnosis of rosacea is made by fulfilling one of several primary and one of many secondary criteria. Primary criteria for rosacea include transient erythema/flushing, persistent facial redness, papules and pustules, and increased facial telangiectasias. Secondary criteria include burning/stinging, elevated red facial plaques with or without scale, dry/scaly skin, persistent facial edema (subtypes of solid facial or soft facial type), phymatous changes, and ocular manifestations such as burning/itching, conjunctival hyperemia, lid inflammation, styes, chalazia, and corneal damage.
    There are four subtypes and one variant of rosacea that have been defined by the National Rosacea Society committee on the classification and staging of rosacea: (i) erythematotelangiectatic, (ii) papulopustular, (iii) phymatous, and (iv) ocular. Erythematotelangiectatic rosacea is characterized by flushing and persistent central facial erythema with or without telangiectasia. The papulopustular type has persistent central facial edema and transient papules, pustules, or both. Phymatous rosacea occurs most often on the nose (rhinophyma) and is characterized by thick skin with an irregular surface, nodularities, and bulbous enlargement. Careful evaluation of a nose with the changes of rhinophyma should be undertaken because basal cell carcinomas may be present, as well as less common tumors. Lastly, the ocular type of rosacea has many symptoms, which will be discussed below. Granulomatous rosacea is a variant characterized by noninflammatory, hard, brown, yellow, or red papules/nodules of the central face. It is of note that rosacea fulminans (pyoderma faciale), steroid-induced acneiform eruption, and perioral dermatitis are not considered rosacea variants but separate entities (1).
    Ocular changes (blepharitis, conjunctivitis, and keratitis) and sebaceous hyperplasia of the nose (rhinophyma) may be associated with ocular rosacea. Differential diagnostic considerations include (i) acne vulgaris, which is characterized by a wider distribution of lesions and the presence of comedones, (ii) periorificial
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    dermatitis, (iii) seborrheic dermatitis, (iv) malignant carcinoid syndrome, (v) lupus erythematosus, and (vi) photodermatoses. Ocular rosacea has been theorized to be secondary to increased local levels of interferon-1α that is proinflammatory and leads to lid irritation and erythema. Lipid breakdown in the tears releases fatty acids that are also irritating. Some studies have also shown a more alkaline pH of tears in patients with rosacea.
    Helicobacter pylori, a microaerophilic gram-negative bacteria implicated in gastric ulcer disease, has been theorized to be the inciting organism in rosacea on the basis of an increased incidence of dyspepsia in this population and the responsiveness of rosacea to metronidazole. Fifty percent of the world’s population and 25% of the US population may have antibodies to this organism. Colonization is associated with increased levels of serum gastrin, which can cause flushing. Also, H. pylori infection can increase levels of histamine, prostaglandins, leukotrienes, and various other cytokines. Therapy to eradicate this organism usually consists of a combination of oral metronidazole, amoxicillin, and omeprazole. Conflicting studies regarding this association with rosacea have recently been in the literature. In general, it is felt that strong support for a link between H. pylori infection and rosacea is lacking (2). Large case control studies would be needed to prove this association because of the high baseline incidence of this exposure.
    Infection with Demodex mites is common, with infection approaching 100% in sensitive tests of healthy adults. Some have hypothesized that infection with Demodex is a cause of rosacea. There is controversy within the literature whether this is the case. In one study, there was a link between higher mite counts and papulopustular but not erythematotelangiectatic rosacea (2). It is unclear whether Demodex is pathologic or just normal skin flora.
  • Perioral (periorificial) dermatitis is a distinct clinical entity that can easily be confused with rosacea, seborrheic dermatitis, eczematous dermatitis, or acne. It primarily affects young women, is usually found around the mouth but occasionally around the nose or eyes, and is of unknown cause; Candida, Demodex, fluorinated toothpastes, chapping, irritation, and oral contraceptives have been implicated. Stinging/burning is usually a more significant complaint than pruritus. Pediatric cases tend to involve more boys and have periocular and perinasal papules. As with rosacea, prolonged use of potent topical corticosteroids can cause an eruption with similar features and can perpetuate preexisting disease.
    Perioral (periorificial) dermatitis is found at a significantly increased rate in atopic individuals. Compared with patients with rosacea, those with perioral dermatitis have significantly increased transepidermal water loss (TEWL) and atopic diathesis (3).
II. Subjective Data
  • The facial lesions of rosacea and perioral (periorificial) dermatitis often cause justifiable concern about personal appearance. There may be a family history of easy flushing and blushing, as well as of a red, ruddy complexion.
  • Rosacea papules and cysts can be painful; perioral (periorificial) dermatitis papules may itch or cause a burning sensation.
  • Patients with rosacea may complain of feelings of facial heat and congestion as well as dry eyes. Other ocular complaints include stinging, photophobia, burning, tearing, scratchiness, and a sense of a foreign body being in the eye. The frequency of ocular symptoms increases as rosacea progresses. Many of these patients have also experienced multiple styes in the past. Individuals who work at video display terminals (VDTs) have complained of symptoms of facial burning and have been found to have a possible increased risk of rosacea.
III. Objective Data
  • Rosacea (See color insert.)
    • Recurrent erythema, located in the middle third of the face (mid-forehead, nose, malar areas, and chin), may later lead to a persistent flush and telangiectasias. Symmetric involvement of the eyelids may be the only presentation. Lupoid or granulomatous rosacea consists of uniform brown-red papules or nodules in the typical rosacea distribution. Fifteen percent of cases of granulomatous rosacea
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      have extrafacial lesions. “Rosacea fulminans” or pyoderma faciale is a separate condition and not a variant or subtype of rosacea, according to the most recent classifications. It usually occurs in women from the age of 15 to 46 with a prior history of seborrhea. It is characterized by rapid onset, giant coalescent nodules on the face without evidence of comedones, telangiectasias, erythema, and remission with little or no scarring.
    • The lesions of rosacea may be seen in the beard region, neck, scalp, shoulders, and upper back.
    • Acneiform papules, pustules, and cysts may be present; comedones are not.
    • Central facial edema of the forehead, eyelids, nose, and cheeks with subsequent enlargement of the soft tissues may be seen.
    • Rosacea may have an associated dermatitis of the central face and cheeks. The differential diagnosis includes seborrheic dermatitis or irritant dermatitis. Often, these patients will decrease the use of soaps to minimize irritation. The surface microbes and lipids are altered, and gentle daily cleansing helps normalize this.
    • Rhinophyma, which predominantly affects men, is associated with follicular dilatation, irregular thickening of the skin, and hypertrophic soft masses centered about the tip of the nose. Pseudorhinophyma can be seen when heavy eyeglasses obstruct the lymphatic and venous drainage from the nose.
    • Fifty percent of patients will have ocular findings including blepharitis, conjunctivitis, iritis, and/or keratitis. The severity of the eye involvement does not correlate with the severity of facial involvement. Hyperplasia and plugging of the meibomian gland, a modified sebaceous gland, likely leads to the symptoms of ocular rosacea. The lid margin may show early hyperemia of the eyelids, conjunctivitis, blepharitis, and, in later stages, granules and yellow papules on the conjunctiva. Features of greater concern requiring referral to an ophthalmologist include keratitis, corneal vascularization, and severe conjunctivitis. Ocular rosacea is a rare cause of blindness.
    • Drugs associated with flushing include vasodilators, calcium channel blockers, cholinergic agents, opiates, cyclosporin, nicotinic acid, tamoxifen, and rifampin. Topical sorbic acid, a common component of cosmetics and corticosteroids, can cause facial redness and itching.
  • Perioral (periorificial) dermatitis
    • Discrete 1- to 3-mm erythematous or flesh-colored papules and pustules, often with a fine scale, are seen singly, in clusters, or in plaques around the mouth, sparing the vermillion border. Lesions may occasionally occur around the nose and on the malar areas below and lateral to the eyes. In 10% to 20% of patients, the disease will extend to the glabella and the periocular region.
    • There is often a persistent erythema of the nasolabial folds that may extend around the mouth and onto the chin.
    • Long-standing lesions show a flatter, more confluent eruption, with superimposed dry scaling.
    • The differential diagnosis includes seborrheic dermatitis, rosacea, contact or irritant dermatitis, nutritional deficiencies, or the rare glucagonoma syndrome.
IV. Therapy
  • Rosacea
    • Precipitating factors. Patients who flush easily should avoid hot food and drinks and activities that induce this change. These may include tea, coffee, sunlight, extremes of heat and cold, and emotional stress. It has been demonstrated that the flushing caused by coffee is induced by a temperature of 60°C and above, but not by cold coffee or caffeine alone. A printed handout with trigger factors is helpful for the individual patient to identify any causative agents for worsening of their rosacea symptoms. If flushing is not caused by these factors, there is no evidence that avoidance will result in improvement of the disease. Vasodilator drugs that affect peripheral blood vessels will also exacerbate rosacea flushing. The vascular reactivity of rosacea flushing may be confused with menopausal flushing and carcinoid flushing.
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    • Systemic therapy
      • The most effective treatment for rosacea is the administration of systemic antibiotics, particularly those in the tetracycline family. The literature supports initial therapy with tetracycline, but doxycycline or minocycline are also quite effective for initial treatment. For tetracycline, therapy should be initiated at 250 mg q.i.d. until symptoms subside, after which the dosage can be decreased slowly or discontinued. Nausea/gastrointestinal upset is a significant side effect of tetracycline therapy. Occasionally, it is necessary to use larger doses (1.5 to 2.0 g daily) for short periods of time to induce remission. Long-term administration is usually needed. Tetracycline is most effective in decreasing the acneiform component and clearing the keratitis but may also diminish erythema. Dosing of minocycline or doxycycline should be initiated at 100 mg b.i.d. and tapered as described earlier.
        After discontinuing tetracycline therapy, 25% of patients can be expected to relapse within a few days; approximately 60% will have a relapse within 6 months. Keratitis always seems to recur quickly and may require continual treatment.
        Ocular rosacea responds to oral tetracyclines or erythromycin. Higher doses may be required initially and then as little as 250 mg q.d. or q.o.d. of either antibiotic may be sufficient. Long-term remissions may occur, requiring episodic oral therapy.
      • If tetracycline is ineffective, minocycline, doxycycline, or erythromycin should be tried. Doxycycline monohydrate has a pH of 7.0, which decreases the chance of gastrointestinal upset, although it is more expensive.
      • Metronidazole (Flagyl) (200 mg b.i.d.) has been shown to be as effective as tetracycline for papulopustular rosacea. Patients must be forewarned of its disulfiram (Antabuse)-like side effects if alcohol is consumed during treatment, as well as an associated peripheral neuropathy with prolonged use.
      • Ampicillin (250 mg b.i.d. to t.i.d.) has also been shown to be useful.
      • Trimethoprim/sulfamethoxazole on a daily basis has a rapid onset of action but has rare associated side effects of bone marrow suppression and toxic epidermal necrolysis (TEN).
      • Clarithromycin (Biaxin) in a dose of 250 mg b.i.d. for 4 weeks and then 250 mg q.d. for 4 weeks is another oral alternative for treatment-resistant patients.
      • Menopause-related flushing or intractable flushing might respond to low doses of clonidine (Catapres), an α-adrenergic agonist, at a dose of 0.05 mg PO b.i.d. or through a transdermal patch. It is otherwise apparently ineffective in rosacea.
      • Isotretinoin (0.5 mg/kg/day for 20 weeks) can be highly effective in patients with severe refractory papulopustular rosacea. There is improvement in edema, erythema, and telangiectasias and a decrease in sebaceous gland hyperplasia, rhinophyma, and oily skin. Ocular side effects of therapy occur more frequently than with acne. One study showed efficacy with as little as 10 mg/day of isotretinoin for 16 weeks. Other dosing regimens include 10 mg two to three times per week or 20 mg two times per week. Remission rates remain to be determined, but some patients note prolonged disappearance of disease. Patients with rosacea are generally older than those with acne, and even more care concerning adverse effects is necessary when using retinoid drugs.
      • Oral spironolactone at 50 mg/day for 4 weeks improved rosacea in 11 of the 13 patients studied. The improvement was hypothesized to be secondary to changes in the metabolism of sex steroid hormones.
      • Rosacea-like demodecidosis can be treated with oral ivermectin and/or topical permethrin cream.
    • Topical therapy for the lesions is similar to that for acne vulgaris
      • Topical 1% metronidazole (MetroGel, MetroCream, and MetroLotion) applied once daily has been shown to decrease inflammatory lesions by 77%
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        over a 15-week period (4). This medication is a good alternative to oral antibiotic use in some patients and can help decrease flares if use is continued after discontinuing oral therapy. The gel formulation has a higher rate of penetration in vitro, but may cause stinging. Paresthesias have been reported with topical metronidazole.
      • Topical erythromycin or clindamycin lotions may be used b.i.d., as in the treatment of acne vulgaris.
      • Preparations containing benzoyl peroxide, sulfur in concentrations of up to 15%, or both benzoyl peroxide and sulfur (Sulfoxyl) can be useful.
        Sulfacetamide-containing antibiotics are available as Sulfacet-R, Plexion cleanser, Plexion TS, Novacet, and Klaron. Sulfacet-R, Plexion, and Novacet are also sulfa based. Sulfa is a good choice in some patients if Demodex are thought to be playing a role. Patients with sulfa allergies should avoid these preparations.
      • Fifteen percent of azelaic acid (Finacea) applied b.i.d. is an alternative or adjunctive therapy in rosacea patients with a low side effect profile. Some stinging can be noted with application. Use of azelaic acid 15% gel twice daily decreased inflammatory rosacea lesions by 80%. In one study, erythema was completely resolved after 15 weeks of therapy in 17.9% of patients (4).
      • Ultraviolet light (UVL) therapy is of no benefit and may worsen symptoms.
      • Topical corticosteroids are occasionally used to decrease erythema and inflammation. The high-potency steroid preparations should never be used, because they might induce more widespread and irreversible telangiectasias. Use of 1% hydrocortisone cream is acceptable.
      • Photodynamic therapy (PDT) has given “excellent” results in one case report. The patient had six sessions of PDT with 5-aminolevulinic acid (5-ALA) (5).
    • Telangiectatic vessels may be destroyed by multiple vascular lasers such as the long pulsed-dye laser (585 to 600 nm), the KTP laser (532 nm) or an intense pulsed light source. Several treatments may be required with each system. Pinpoint electrosurgery using the epilating needle is also an option but carries an increased risk of scarring when compared with current laser options. In one study, the pulsed-dye laser also reduced the number of papules and pustules by 60%; the intense pulsed light source is also being used to treat both the inflammatory and vascular components of rosacea.
    • Ocular rosacea with associated blepharitis can be treated with topical antibiotic bacitracin/polymyxin B. The lid margins can be gently scrubbed with baby shampoo on a cotton-tipped applicator, commercially available lid scrubs, or a nonabrasive gauze pad impregnated with a surfactant cleanser. Warm compresses q.i.d. are helpful in removing adherent crusts. If significant inflammation is present, a topical steroid ointment can be applied to the eyelid margins on only a short-term basis.
    • Surgical reduction of the soft tissue enlargement in rhinophyma may be accomplished by CO2 laser surgery, a surgical shave, dermabrasion, or electrosurgery.
    • Cosmetic lotions and foundations with a green tint help to camouflage the redness and telangiectasias of rosacea. Estée Lauder, Origins, and Prescriptives have a broad choice of these green-based cosmetics.
    • Use of mild nonsoap cleansers as well as a SPF 15 sunscreen that protects against ultraviolet A (UVA) and UVB are recommended on a daily basis. To minimize irritation, 30 minutes should elapse after washing before applying topical products. Cool compresses, gel masks, sucking of ice chips, central facial massage, biofeedback, and flaxseed oil are all nonstudied alternative therapies.
    • A list of multiple foods is available to determine what items may be trigger factors for rosacea. The National Rosacea Society is an excellent general resource for both patients and providers at 1-888-662-5874 or http://www.rosacea.org.
  • Perioral (periorificial) dermatitis
    • Systemic antibiotics used as described for rosacea are the only reliable therapy. Perioral (periorificial) dermatitis usually clears within 3 to 8 weeks, and it is then often possible to taper off antibiotics. There is moderate support in the literature
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      for the efficacy of tetracycline use in treatment of perioral dermatitis. Dosing is the same as that used for rosacea. Some patients need longer-term maintenance therapy.
    • Isotretinoin has been successful in treating granulomatous perioral dermatitis.
    • Topical therapy can be helpful.
      • Topical therapy with the antibiotics previously described, including metronidazole, may be helpful. One study found topical MetroGel to be an effective topical therapy in children with perioral dermatitis (6).
      • Fluorinated corticosteroids must be avoided assiduously. Hydrocortisone 1% or other nonfluorinated corticosteroid cream may be of symptomatic benefit and can be helpful in the transition from higher potency topical steroid abuse to topical or oral antibiotic therapy but will not cure the eruption.
      • PDT with 5-ALA and blue light activation was shown to have a 92% clearance of perioral dermatitis versus topical clindamycin (81% clearance) in a split face study of 14 individuals (7).
      • Azelaic acid 20% cream applied twice daily has been helpful in clearing perioral dermatitis. In one series, ten patients applied the cream b.i.d. Response was seen within 2 to 6 weeks, with complete clearance of the perioral dermatitis in all patients. There was no observed recurrence after 10 months (8).
References
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 2002;46:584–587.
2. Crawford GH, Pelle MT, James WD. Rosacea: I. etiology, pathogenesis, and subtype classification. J Am Acad Dermatol 2004;51:327–341.
3. Dirschka T, Szliska C, Jackowski J, et al. Impaired skin barrier and atopic diathesis in perioral dermatitis. J Dtsch Dermatol Ges 2003;1:199–203.
4. Wolf JE, Kerrouche N, Arsonnaud S. Efficacy and safety of once-daily Metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in the treatment of rosacea. Cutis 2006;77:3–11.
5. Katz B, Patel V. Photodynamic therapy for the treatment of erythema, papules, pustules, and severe flushing consistent with rosacea. J Drugs Dermatol 2006;5:6–8.
6. Miller SR, Shalita AR. Topical metronidazole gel (0.75%) for the treatment of perioral dermatitis in children. J Am Acad Dermatol 1994;31:847–848.
7. Richey DF, Hopson B. Photodynamic therapy for perioral dermatitis. J Drugs Dermatol 2006;5(2 Suppl):12–16.
8. Jansen T. Azelaic acid as a new treatment for perioral dermatitis: results from an open study. Br J Dermatol 2004;151:933–934.
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