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doi: 10.3810/pgm.2010.01.2107
Postgraduate Medicine: Volume 122: No.1
A Review of the Diagnosis and Treatment of Rosacea
Noah Scheinfeld, MD, JD And Thomas Berk, BA
Copyright 2011 All rights reserved. Cover and contents may not be reproduced in whole or in part without prior written permission. Postgraduate Medicine is a registered trademark of JTE Multimedia, LLC. Sending and distribution of any document from this site is strictly prohibited either for free and or a service fee, and will be sited as a violation of copyright under the laws of THE UNITED STATES OF AMERICA

Abstract: Rosacea is a common chronic inflammatory disease of the skin and is associated with a number of etiological causes and inciting factors. It is characterized by erythematous changes of the facial skin, and commonly presents with papules, pustules, or telangiectasias. The 4 subtypes of rosacea are categorized according to secondary symptoms, such as pain, erythema, dryness, and edema. A number of therapies are available to treat rosacea, some of which can be used in combination. The mainstays of therapy are topical metronidazole, topical azelaic acid, and oral tetracyclines. Other pharmacotherapeutic interventions have been shown to improve the signs and symptoms of rosacea, although many of these have not yet received approval by the US Food and Drug Administration for this indication.

Keywords: rosacea; inflammatory disease; pharmacotherapy; dermatological conditions

Introduction

Rosacea is a chronic, relapsing, and remitting progressive inflammatory disease of the facial skin, affecting up to 10% of the population.1 It is caused by an inflammatory process involving the vasculature and pilosebaceous units, leading to the development of an erythematous eruption, with symptoms of pain, burning, and flushing. This underlying inflammation also causes increased sensitivity of the skin and lowers the threshold of irritability to topical therapeutic agents.

Clinical Signs and Symptoms

Patients with rosacea generally present with complaints of flushing, itching, and sensitive skin. The facial skin is erythematous, with an overlying eruption of papules, pustules, and erythematous plaques, especially in chronic cases. This eruption can vary in different racial groups, with papules and pustules being less common in African Americans, who more commonly develop the granulomatous variant of rosacea.2,3 Involvement of extrafascial areas, such as the neck, upper chest, and scalp have been observed, but are uncommon manifestations of disease thought to be associated with chronic sun exposure and damage.4 A number of triggering factors have been associated with the development and flaring of rosacea (Figure 1).5-8

View: (Figure 1 ) - Triggering factors associated with the development and flaring of rosacea.
Diagnosis

An expert committee assembled by the National Rosacea Society stated that rosacea should be diagnosed only when ≥ 1 of these features are present on the convex areas of the face: transient erythema or flushing, nontransient erythema, papules, pustules, and telangiectasias.9 Secondary signs and symptoms of rosacea include burning, stinging, edema, ocular manifestations, dryness, and phymatous changes. These secondary symptoms of rosacea are used to classify patients into 1 of the 4 subtypes.4

Subtypes and Variants

Erythematotelangiectatic rosacea (ETR) is associated with prolonged flushing of the face, generally > 10 minutes, usually associated with stimuli, such as emotional stress, hot drinks, spicy foods, exercise, and temperature changes.5-8 The erythema of ETR is most intense in the central portions of the face, sparing the periocular areas. These patients generally have a decreased threshold of irritation from topical substances, and can develop severe burning or itching. Their skin is usually drier than the skin of other subtypes.

Papulopustular rosacea is seen mainly in middle-aged women, and is characterized by the presence of an area of erythema in the central portions of the face, with overlying papules and pinpoint pustules. Flushing may occur in papulopustular rosacea, but in a milder form than that found in ETR.

Phymatous rosacea is characterized by the presence of phymata, which are solitary and coalescent, leading to marked thickening of the skin. These are most commonly seen on the surface of the nose (rhinophyma), but can also be present on the chin, forehead, ears, or eyelids. Unlike the other subtypes of rosacea, treatment of phymata often requires surgical intervention.10,11

Ocular rosacea is characterized by ocular and periocular findings, which include blepharitis and conjunctivitis, and can eventually lead to keratitis, scleritis, or iritis. Patients with ocular rosacea may complain of a burning or itching sensation, increased light sensitivity, and a foreign body sensation. The ocular manifestations of rosacea can precede the more generalized symptoms by many years.

Aside from the above-mentioned subtypes, 3 other variants of rosacea are: rosacea fulminans, granulomatous rosacea, and steroid rosacea. Rosacea fulminans is a severe form of disease with the development of papules, nodules, and discharging cysts. This is associated with inflammatory bowel disease on rare occasions. Granulomatous rosacea, more prevalent in African Americans, manifests as firm nodules similar to those seen in cutaneous sarcoidosis and tuberculosis. Steroid-induced rosacea is most commonly associated with the chronic use of topical steroids. These agents transiently improve the signs and symptoms of rosacea which flare when the topical steroid is withdrawn, leading to topical steroid addiction syndrome.

Differential Diagnosis

A number of dermatological conditions can mimic the subtypes and variants of rosacea, and their presence should be excluded before reaching a definitive diagnosis (Figure 2). Acne vulgaris is a very common disease of the skin in adolescents and older adults, which is associated with the formation of inflammatory pustules and papules and, in severe disease, nodules and cysts on an erythematous base (Figure 3). The inflammatory lesions of acne can easily be confused with ETR and papulopustular rosacea, but are distinguishable based on the presence of telangiectasias and the later age of onset in rosacea. Erythematous skin in the central face can also be seen in seborrheic dermatitis. Seborrheic dermatitis, however, generally does not spare the periocular areas, commonly shows eczematous changes, and may be associated with a greasy scale, distinguishing it from the subtypes and variants of rosacea.

View: (Figure 2 ) - Dermatological conditions to be excluded for accurate diagnosis of rosacea.
View: (Figure 3 ) - Clinical and laboratory features of rosacea.

The eruption associated with contact dermatitis can also mimic the inflammatory changes seen in rosacea; the symptoms of pain, burning, and itching can be seen in both entities. Photodermatitis can present as inflammatory changes in the form of papules and plaques, and can also be difficult to distinguish from rosacea. These conditions can be differentiated, however, on the basis of a history of causative factors—the application of an irritant or allergic agent in contact dermatitis, and sun exposure in photodermatitis. Histology can also differentiate these processes, as contact and photodermatitis will show spongiosis and parakeratosis, whereas in rosacea the presence of perivascular infiltrates of lymphocytes and, rarely, plasma cells predominates, with well-circumscribed collections of epithelioid histiocytes, usually in peri-infundibular locations. Rosacea demonstrates very nonspecific findings on dermoscopy, such as the presence of edema and telangiectasias.

Systemic diseases associated with facial flushing or eruption may also be confused with rosacea. Diseases such as polycythemia vera, mastocytosis, superior vena cava syndrome, and carcinoid syndrome are associated with symptoms of facial flushing, and should be distinguished from rosacea based on history and laboratory findings. Systemic lupus erythematosus, dermatomyositis, and mixed connective tissue disease are all associated with facial eruptions, which may look similar to those seen in ETR and papulopustular rosacea, and must also be distinguished. Laboratory studies can help to distinguish these entities from rosacea—a positive antinuclear antibody, elevated erythrocyte sedimentation rate or C-reactive protein, as well as seropositivity of a number of intranuclear or intracytoplasmic particles (eg, anti-Ro, anti-dsDNA) would all be more commonly found in connective tissue disorders rather than in rosacea.

Treatment

Therapy for the treatment of rosacea is not curative, and is best measured in terms of reduction in the amount of erythema and inflammatory lesions, decrease in the number, duration, and intensity of flares, and concomitant symptoms of itching, burning, and tenderness. The 2 primary modalities of rosacea treatment are topical and oral antibiotic agents. Other nonmedical treatments have also been beneficial, and each of these modalities will be discussed below.

Topical Therapy

The major topical antibiotics used to treat rosacea are clindamycin, erythromycin, and metronidazole. Other topical therapies include azelaic acid, pimecrolimus, and sulfacetamide sulfur, antiparasitics, and alpha-agonists.

Antibiotics

Topical metronidazole has shown greater efficacy than placebo in a number of clinical trials.12-15 It is considered a mainstay of rosacea treatment, and is generally well tolerated. Topical clindamycin, erythromycin, and combination benzoyl peroxide-clindamycin may also be used, but they are not US Food and Drug Administration (FDA) approved for the treatment of rosacea.

In comparing topical metronidazole with azelaic acid, one randomized trial showed that the efficacy of azelaic acid was significantly greater than metronidazole in terms of improving erythema and inflammation, but was also associated with a greater potential for irritation.16-18 Another nonantibiotic topical agent is the immunomodulator pimecrolimus, which was shown in its pilot study to cause clearing of the skin in 50% of patients after 6 weeks, while another randomized trial demonstrated that pimecrolimus was no more effective than the vehicle when used for 4 to 6 weeks.19,20 Anecdotal evidence suggests that this anti-inflammatory agent may rarely produce a syndrome similar to steroid-induced acne.21,22

Other topical pharmacotherapies to treat rosacea may include the vitamin A retinoid class of drugs, such as adapalene and retinaldehyde creams. These creams should theoretically show benefit in treating the underlying causes of rosacea, although they have not yet been extensively studied in trials.23 The mechanism of action of the retinoid class of drugs is via regulation of the retinoic acid receptor, an important regulator of keratinocyte proliferation, cell differentiation, and inflammation.24 A small study has also demonstrated the efficacy of topical vitamin C for rosacea, suggesting the possibility that free radical production may play a significant role in the inflammatory response of rosacea.25

Topical use of selective alpha-agonist agents may be of additional help, as the erythema and flushing associated with ETR may be related to abnormalities in specific alpha-receptor genotypes. One study showed significant benefit with the use of the alpha-agonist oxymetazoline in reducing the flares and the inflammatory symptoms in patients with medication-resistant ETR.26 One small case study showed some efficacy with the use of the chloride salt 1-methylnicotinamide when applied for 2 to 4 weeks.27

Some antiparasitic drugs have been observed to be helpful as both oral and topical agents in the treatment of the inflammatory response of rosacea. Oral ivermectin and lindane have shown some efficacy in the eradication of Demodex folliculorum, one possible factor that may lead to the inflammation underlying rosacea.3 Permethrin and crotamiton topically have not shown great usefulness in eradicating Demodex folliculorum, but may still lead to the resolution of some of the underlying inflammation.

Oral Therapy
Antibiotics

Tetracyclines are the mainstay of oral pharmacotherapy for the treatment of rosacea, with positive effects being seen at a tetracycline dose of 250 to 500 mg twice daily. Doxycycline and minocycline are commonly used oral therapies because of their bioavailability, ease of use, and once-daily dosing.28 Azithromycin has also been shown to be beneficial for treating rosacea, is better tolerated than many of the tetracyclines, and can be dosed 3 times a week.29,30 A significant amount of circumstantial evidence links the eradication of Helicobacter pylori and the successful treatment of rosacea, including the use of “triple therapy,” consisting of omeprazole and 2 of the following antibiotics: clarithromycin, amoxicillin, or metronidazole.31 Other oral antibiotics that have shown efficacy in rosacea treatment include penicillin, erythromycin, amoxicillin, ampicillin, dapsone, as well as oral metronidazole.32-36 Although not commonly used, these other oral antibiotics are useful when topical therapies are not well tolerated and there are contraindications to the use of tetracyclines (eg, erythromycin during pregnancy).

Combining topical and oral antibiotics has been shown to be effective, as together they can have anti-inflammatory properties. An especially effective combination is topical metronidazole 1% and oral doxycycline, which has been shown to be well tolerated and to decrease lesion counts.37

Isotretinoin, although not working directly as an antibiotic, has strong antibacterial effects.38 The effectiveness of isotretinoin has been shown particularly in younger adults and those with less severe stages, and it has also been shown to reduce phymatous changes.38 Other oral therapies that have shown benefit are spironolactone, prednisone, certain psychoactive drugs, β-blockers, ondansetron, and cyclooxygenase-2 inhibitors.39,40 Hormonal therapy for the treatment of rosacea may be accomplished by the use of the oral contraceptive chlormadinone acetate/mestranol, as well as the antiandrogen cyproterone.3,41,42

Non-Medical Therapy

Phototherapy has been shown to be useful in the treatment of rosacea. Multiplexed laser therapy has been shown to reduce the erythema and telangiectasias associated with rosacea, while intense pulsed light appears to be of particular benefit for ETR.43,44 Telangiectasias of the face can also be treated with a long pulsed dye laser or a potassium-titanyl-phosphate laser.3

Sun avoidance and the regular use of sunscreen have been shown to be of particular benefit in the restoration of normal skin, especially when used with regular moisturizers.45 Another topical therapy that has been shown to help restore the skin’s barrier is kinetin, a plant cytokinin that is available as a 0.1% lotion.46 The Chinese herb Chibixiao has also been found helpful in the treatment of rosacea in at least one trial.47

In addition, patients with rosacea should be counseled to adhere closely to their therapy, and to avoid triggering factors. Patients should be told about the importance of avoiding various types of makeup, as well as abstinence from alcohol, if either of those were factors in their particular disease processes.

Conclusion

The medications mentioned above have some benefit in rosacea treatment, but the mainstay of therapy remains topical metronidazole or azelaic acid and oral tetracyclines. As this disease process causes increased skin sensitivity, many of the topical therapies may not be well tolerated, necessitating other therapies. It is therefore important to have as many treatment options as possible. As our review has shown, rosacea can be a disfiguring disease which can be difficult to treat. Providers should provide counseling for the psychological stress that often accompanies this condition.



Conflict of Interest Statement
Noah Scheinfeld, MD, JD and Thomas Berk, BA disclose no conflicts of interest.
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Noah Scheinfeld, MD, JD 1
Thomas Berk, BA 2

1New York University Medical Center, New York, NY 2Columbia University, New York, NY

Correspondence: Noah Scheinfeld, MD, JD, 150 West 55th St., New York, NY 10012.
Tel: 212-991-6490,
Fax: 646-349-2493,
E-mail: scheinfeld@earthlink.net
Disclaimer
In an effort to provide information that is scientifically accurate and consistent with accepted standards of medical practice, the editors and publisher of Postgraduate Medicine routinely consult sources believed to be reliable. However, readers are encouraged to confirm this information with other sources. For example and in particular, physicians are advised to consult the prescribing information in the manufacturer's package insert before prescribing any drug mentioned.




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