Lecture Notes: Acne Rosacea

Rosacea is an acneiform disorder of middle-aged and older adults characterized by vascular dilation of the central face, including the nose, cheek, eyelids, and forehead. The disease is chronic; control rather than cure is the goal of therapy.

EPIDEMIOLOGY of Acne Rosacea
  • Rosacea most commonly occurs in patients between the ages of 30 and 60 years, although it has been reported in younger individuals. 
  • It is relatively common among individuals with fair skin and light hair and eye color, and among those who experience frequent blushing or flushing.

PATHOGENESIS of Acne Rosacea
  • The cause of vascular dilatation in rosacea is unknown, although factors that trigger innate immune responses may worsen symptoms. 
  • The hair follicle mites Demodex folliculorum and Demodex brevis have been thought to play a role in the pathogenesis of the inflammatory lesions; this hypothesis is supported by studies that have found increased numbers of mites in the skin of patients with rosacea compared with unaffected individuals. On the other hand, in a study of patients with rosacea treated with tetracycline for one month, mite counts did not decrease despite an improvement in rosacea symptoms.
  • Staphylococcus epidermidis has been cultured from lesional skin in patients with papulopustular rosacea. However, additional studies are necessary to determine whether S. epidermidis is involved in the pathogenesis of this disorder.

The spectrum of clinical findings includes the following:
  • Patients with rosacea have an increased susceptibility to recurrent flushing reactions that may be provoked by a variety of stimuli including hot or spicy foods, drinking alcohol, temperature extremes, and emotional reactions.
  • The earliest stage of rosacea is characterized by facial erythema (particularly on the nose and cheeks, but also on the forehead, chin, and occasionally the neck) and telangiectasias (typically on the cheeks). Patients may report worsening of erythema by heat or sunlight, and by ingestion of alcohol or offending foods. 
  • Patients with rosacea may develop severe sebaceous gland growth that is accompanied by papules, pustules, cysts, and nodules. Inflammatory lesions develop in the areas of erythema and appear identical to the inflammatory lesions of acne vulgaris, with the exception of a lack of comedones in rosacea. Some patients experience burning or stinging sensations
  • Ocular symptoms occur in many patients with rosacea, most commonly in combination with skin symptoms, but occasionally alone. Eye involvement may include foreign body sensation and burning, telangiectasia and irregularity of lid margins, meibomian gland dysfunction (posterior blepharitis), keratitis, conjunctivitis, and episcleritis. 
  • Rhinophyma is hyperplasia of the soft tissues of the nose that tends to occur late in the course of rosacea, most commonly in middle-aged men.

An expert panel suggested classifying rosacea into four broad subtypes to aid diagnosis and treatment:
  • Erythematotelangiectatic — Characterized by flushing in response to embarrassment, exercise, or hot environments, and with associated symptoms of stinging and burning, particularly after applying topical preparations. 
  • Papulopustular (Classic) — Characterized by small papules and pinpoint pustules, with a red central portion of the face and sparing of the periocular, and sometimes of the perioral, skin. 
  • Phymatous — Characterized by marked skin thickening and surface nodularities, which can occur on the nose, chin, forehead, ears, or eyelids. 
  • Ocular — Characterized by blepharitis and conjunctivitis, often in conjunction with or following other skin findings.

A subsequent review proposed an additional subtype:
  • Glandular — Characterized by sebaceous gland hyperplasia. There may be large edematous papules and independent pustules, and nodulocystic lesions may be present. Periocular sparing is typical.

Progression from one subtype to another is unusual, except that severe papulopustular and glandular rosacea may progress to phymatous rosacea.

DIAGNOSIS of Acne Rosacea
The diagnosis of rosacea is based upon clinical findings; there are no specific diagnostic tests. The National Rosacea Society Expert Committee on the classification and staging of rosacea has developed provisional diagnostic guidelines for rosacea. The guidelines recommend the presence of one or more of the following primary features:
  • Flushing (transient erythema). 
  • Nontransient erythema. 
  • Papules and pustules. 
  • Telangiectasia.

In addition, one or more of the following secondary features often appear with the primary features listed above, although can occur independently in some patients:
  • Burning or stinging. 
  • Plaque. 
  • Dry appearance. 
  • Edema. 
  • Ocular manifestations. 
  • Peripheral location. 
  • Phymatous changes.

Differential diagnosis 
A number of disorders are in the differential diagnosis of rosacea.
  • Rosacea is distinguished from acne vulgaris by the propensity of the latter to occur in younger patients, and the presence of comedones (blackheads and whiteheads), lack of flushing, and lack of significant background erythema with acne vulgaris. The key is the absence of comedones with rosacea. 
  • Patients with seborrheic dermatitis may lack acneiform lesions despite scales around the nose, eyebrows, ears, and scalp. Many patients with acne rosacea have concurrent seborrheic dermatitis.  
  • Patients with demodicosis can present with facial erythematous, inflammatory papules that closely resemble rosacea. A potassium hydroxide preparation will reveal Demodex mites. Immunosuppressed patients are susceptible to demodicosis, though the disorder may also be seen in healthy individuals. Increased numbers of Demodex mites may also be seen in cases of true rosacea; however, the association between the Demodex mite and rosacea remains unclear. 
  • The carcinoid syndrome is rare. Patients experience flushing and may develop venous telangiectasias of the central facial area that can be confused with rosacea lesions. The flushes of rosacea tend to last longer than the very brief 20 to 30 second flushes characteristic of carcinoid. 
  • Systemic lupus erythematosus is associated with a facial rash and can also be aggravated by light, but there is an absence of papules and pustules in the presence of systemic complaints. 
  • Use of chronic topical glucocorticoids on the face can cause a facial eruption that is indistinguishable from rosacea. Treatment includes discontinuation of glucocorticoid therapy in combination with oral tetracycline or topical pimecrolimus.

TREATMENT of Acne Rosacea
A systematic review found that most studies of treatments for rosacea were of poor quality. The review found that topical metronidazole and azelaic acid are effective, and found some evidence that oral metronidazole and tetracycline are also effective.

The key to treating rosacea is the knowledge of the treatment goal, which often is control rather than cure of the chronic disease. Inflammatory and ocular lesions typically respond well to therapy; facial erythema tends to be more resistant.

Initial therapy
All patients with rosacea should receive initial patient education about the use of mild cleansers, the avoidance of irritants, and the use of broad spectrum sunscreens.

1) Topical antimicrobials and benzoyl peroxide — Topical antimicrobial agents or benzoyl peroxide are the initial treatments of choice to relieve the inflammatory lesions of rosacea. For papular and pustular lesions, a thin layer of one of the following is applied to the entire involved area, not just to individual lesions, once or twice daily:
  • Metronidazole is frequently used as initial therapy with or without a short course of oral antibiotics. The 1 percent gel is typically applied daily, whereas the 0.75 percent cream, the lotion, and the 0.75 percent gel are typically applied twice a day. The recommendation for twice daily dosing was derived primarily from pharmacokinetic findings rather than clinical data. One clinical study has found that the 1 percent and 0.75 percent cream were comparable in reducing inflammatory lesion counts and erythema, and that once daily dosing resulted in a 60 percent fall in lesion counts. There are no studies comparing once with twice daily dosing, but once daily dosing can be considered, particularly in patients in whom compliance is an issue. 
  • Azelaic acid is a naturally occurring dicarboxylic acid with antimicrobial and antiinflammatory properties. Azelaic acid 20 percent cream twice daily is useful in treating mild to moderate rosacea; the efficacy of this drug was comparable to 0.75 percent metronidazole cream twice daily in one controlled trial. Azelaic acid 15 percent gel twice daily also appears to be effective; a 15-week randomized trial in 251 patients with moderate papulopustular facial rosacea that compared this formulation with 0.75 percent metronidazole gel found a greater reduction in lesions with azelaic acid (-12.9 versus -10.7). However, fewer patients rated the tolerability of therapy with azelaic acid as "good" or "acceptable despite minor irritation" (89 versus 96 percent), and more patients discontinued azelaic acid because of adverse events (4 versus 0 percent). 
  • Sodium sulfacetamide 10 percent/sulfur 5 percent lotion; clindamycin 1 percent solution, gel, or lotion; and erythromycin 2 percent solution are useful, twice daily, but somewhat less effective than the above therapies.Benzoyl peroxide 2.5 percent once or twice daily, increasing to 5 or 10 percent, can be added if the patient does not experience unacceptably dry skin.

These agents must be used for at least four to six weeks before assessing effectiveness. Combination products (eg, benzoyl peroxide and erythromycin, benzoyl peroxide and clindamycin) are increasingly available. Such products may be useful in improving patient compliance.

2) Acaricides — Since Demodex mites may have a role in the pathogenesis of rosacea, agents that kill mites might be of benefit. A study of permethrin cream (5 percent) applied twice a day suggested some benefit for rosacea as well as a decrease in the number of mites found on skin scraping. Although this study reported that permethrin was as effective as metronidazole, it was not properly designed to reach such a conclusion. Treatment with permethrin requires further study before it can be recommended.

Persistent symptoms
1) Topical retinoids — Tretinoin cream (0.025 percent, 0.05 percent, 0.1 percent [20,45 g]) is indicated in patients with papular or pustular lesions that are unresponsive to the above. Always start with 0.025 percent cream or 0.04 percent microgel, two to three times per week at bedtime, gradually increasing to nightly use. Tretinoin may be used in combination with topical antibiotics, especially for recalcitrant disease. Adapalene (available in cream, gel, or lotion) also may be beneficial for the treatment of inflammatory lesions.

2) Oral antibiotics — Oral antibiotics are particularly useful in patients with nodular rosacea, and also are indicated in patients with ocular symptoms, remembering that it may take up to six weeks for improvement to occur with topical therapy alone. Oral therapy combined with topicals may be useful initially for control of rosacea, then tapering the oral medication. Oral therapy consists of the following:
  • Tetracycline 250 to 500 mg by mouth twice a day, doxycycline 50 to 100 mg by mouth once a day to twice a day. Lower doses of doxycycline (eg, 20 mg twice a day or 30 mg immediate release plus 10 mg delayed release taken once daily taken as a single pill) may also be effective and might cause less antibiotic resistance. After four weeks of control, attempt to gradually taper the dosage over the next four weeks to the minimum that will control the disease. Long-term therapy may be required. 
  • Erythromycin 250 mg by mouth twice a day to four times a day and minocycline 50 to 100 mg by mouth once a day are alternative oral antibiotics.

Maintenance therapy 
The chronicity of rosacea requires that medical therapy be continued long-term, not just for flare-ups of the condition. Topical metronidazole administered once a day is effective for maintaining remission in many patients. Those who require oral medications should have the drug tapered to the lowest effective dose possible. Flares during maintenance may require resumption of or higher doses of antibiotics for several weeks on a PRN basis. 


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