Rosacea, from the Latin word rosaceus (meaning rose colored), is a chronic skin condition that is believed to affect up to 14 million Americans.1 This condition has been a documented medical problem since the 14th century. Historically, treatment options consisted of blood letting, application of leeches, topical mercury, and sulfur and blood salves.2 Though significant advances in rosacea management have occurred over the years, rosacea is still underdiagnosed. According to a recent survey by The National Rosacea Society (NRS), only three-quarters of respondents reported receiving a correct diagnosis the first time they sought treatment for their condition. Eighty-six percent of those surveyed reported that their rosacea was diagnosed by a dermatologist, while 10% were diagnosed by a general practitioner, and 2% by an ophthalmologist. An additional 2% were diagnosed by another medical specialist (gynecologist, allergist, rheumatologist, and optometrist).3 These findings suggest that there is a need for greater awareness of those most at risk for developing rosacea, as well as potential signs and symptoms to facilitate accurate diagnosis and treatment.
Demographically, women are more likely than men (3:1) to develop the disorder, or at least to seek medical care for the condition. However, men are more likely to suffer sebaceous gland hyperplasia and phymas.4 Rosacea occurs most often in fair-skinned individuals of northern and eastern European ancestry. While not as common, it is also observed in people of Asian, Hispanic, and African descent, and even in children.5 Although not life-threatening, rosacea can have a significant impact on a patient's self-esteem and quality of life. Another survey by the NRS found that 70% of rosacea patients felt the condition contributed to low self-esteem and poor self-confidence. In addition, the disorder negatively affected their professional interactions.6,7 Unfortunately, these patients suffered unnecessarily because rosacea is a condition that can be easily diagnosed and effectively treated in most patients.
Etiology
Although a plethora of research exists, and several theories have been proposed, the exact cause of rosacea is unclear. Current theories suggest that rosacea pathogenesis is a component of genetic predisposition, psychogenic, and environmental factors, inflammation, and vascular dysfunction. The underlying genetic component may be combined with certain environmental factors that further cause inflammation, as well as vascular instability and proliferation. Emotional stress is thought to play a role in instigating the flare-ups of rosacea.8 In addition, vascular and hormonal factors may prove to be equally important. Specifically, migraine headaches (which are three times more common in patients with rosacea) and menopause (with its documented vasomotor fluctuation) both support a vascular pathogenesis for rosacea.4
Earlier research suggests that Helicobacter pylori may contribute to the development of rosacea by synthesizing gastrins, which may stimulate flushing.9,10 However, study results have been inconsistent, and there is no general agreement on the role of H. pylori in the etiology of rosacea.
The hair follicle mite Demodex folliculorum is often present in increased numbers within the sebaceous ducts and follicles of skin affected by rosacea. These mites may provoke inflammatory or allergic reactions, or act as vectors for microorganisms that instigate papule or pustule formation in rosacea.11 However, it is difficult to establish the pathogenicity of these organisms due to their universal presence in the general population.12,13 Therefore, studies have not been able to confirm these previous hypotheses.
Several plausible possibilities have been suggested, however results from current studies are inconclusive. Therefore, more research is needed to elucidate the pathogenesis of rosacea (research grants are available from the NRS). When a specific etiology is identified, evidence-based therapies can be developed to assist in providing rational treatment options tailored to specific patient populations.
Diagnosis
Unfortunately, diagnostic tests for rosacea do not currently exist. Hence, skin biopsy and laboratory testing do not help establish a diagnosis of rosacea. Instead, practitioners diagnose the disease by its clinical signs, symptoms, and physical appearance.14 A careful, focused history, supported by cutaneous findings, often assists the practitioner in the rosacea diagnosis. At the initial visit, ask patients what factors they associate with flushing to elicit a history of provocative factors, followed by questions about what (if anything) alleviates the flushing. Responses to these questions generally facilitate a focused differential diagnosis and reveal flushing related to alcohol, medications, eating, and/or environmental stimuli.12 In many cases, aggravating factors are identified when the patient keeps a 2-week diary of factors associated with flushing (complimentary diaries may be obtained from The NRS at http://www.rosacea.org or 1-888-NO-BLUSH).
Signs and Symptoms
Blushing as a symptom of rosacea can be observed in childhood, although the usual age of diagnosis is in people between the ages of 30 and 60 years.11 For a diagnosis of rosacea, a patient must have one or more primary features (flushing, transient erythema, nontransient erythema (persistent redness), papules or pustules, or telangiectases (tiny blood vessels). The following secondary features often appear with one or more of the primary features of rosacea but are not necessary for a diagnosis: burning or stinging, plaque, dry appearance, edema, ocular manifestations, peripheral location, and phymatous changes.15
In 2002, an expert consensus committee for The NRS developed a Standard Classification System for rosacea. The classification consists of four main subtypes and one variant (see Table: "Subtypes and Variants of Rosacea"). The primary goal was to create specific criteria for diagnosis and classification that could serve as a reference in clinical practice. This new system proposed criteria on the basis of morphologic characteristics, avoiding assumptions about pathogenesis and disease progression. A secondary goal of the new system included facilitating communication among a broad range of healthcare providers and researchers.15
Primary features of rosacea identified are: flushing, erythema, papules, pustules and telangiectasia. At least one of these features (with a central face distribution) must be present for a diagnosis of rosacea. Differences in severity may occur within each of the subtypes and some patients may have features of more than one subtype simultaneously (see Figure: "Faces of Rosacea").
Subtype 1
Erythematotelangiectatic rosacea describes predominantly flushing and persistent central facial erythema. Telangiectases may or may not be present, as well as edema, stinging and burning, plaque formation or scaling.12,15
Subtype 2
Papulopustular rosacea includes persistent central facial erythema with papules, pustules, or both. This subtype resembles acne vulgaris without comedones. However, rosacea and acne may occur together, and in this case the patient will have comedones as well as the papules and pustules of rosacea. This subtype often occurs in combination with erythematotelangiectatic rosacea. Telangiectases may be present, and are often more visible after successful treatment of erythema, papules, and pustules.12,15
Subtype 3
Phymatous rosacea indicates thickening skin, irregular surface nodularities, and enlargement. The most common phymatous type is rhinophyma (nose), but other locations may be affected, including the chin (gnathophyma), forehead (metophyma), cheeks, and ears (otophyma).16 This type may occur independently after or in combination with the previous two subtypes.15
Subtype 4
A fourth subtype is ocular rosacea. The prevalence in patients with rosacea is as high as 58%, with approximately 20% of these patients developing ocular symptoms before the skin lesions.5,11 Ophthalmic complications may occur in patients with mild skin disease and in fact, eye changes are independent of severity of rosacea. Chronic inflammation of the eyelid margins is the most common ophthalmic sign of rosacea. Patients may also complain of pain and photophobia. Ocular symptoms are usually nonspecific, but include burning, stinging, tearing, and foregn body sensation. Ocular involvement may also include contact lens intolerance, chronic staphylococcal lid infection, conjuctivitis, erythema and scaling of eyelid margins, and corneal neovascularization.4,17 Rosacea keratitis is rare, but if left untreated, may progress to corneal ulceration, scarring, and blindness.17 Thus, patients who have ocular rosacea should be examined by an ophthalmologist yearly for the presence of other, often subclinical complications.
Differential Diagnosis
Rosacea vs. Acne
In differentiating between rosacea and acne, consider the presence of flushing, the distribution and nature of lesions, and the age of the patient. In contrast to acne, rosacea most prominently affects the central face, features telangiectasia, and never involves comedones.13 Finally, rosacea tends to affect older adults while acne is more common among adolescents and young adults.14
Rosacea vs. Carcinoid Syndrome
Carcinoid syndrome, which occurs as a result of a tumor that secretes serotonin and prostaglandins, may also be characterized by watery diarrhea, bronchospastic attacks, abrupt hypotension, edema, and ascites. Further, the flushing due to carcinoid syndrome can be quite intense and is often accompanied by facial edema. In contrast to carcinoid syndrome, the 24-hour urinary excretion of 5-hydroxyindoleacetic acid is normal in rosacea.4,16
Rosacea vs. Lupus Erythematosus
Lupus erythematosus differs from rosacea in onset, flushing history, distribution, and general medical history. Lupus presents acutely with a livid color with sharp margination. Unlike rosacea, flushing and papules are usually not present. Also, antinuclear antibody evaluation can help differentiate lupus from rosacea. Lupus would be suspected with an elevated titer level.4,10
Rosacea vs. Perioral Dermatitis
Perioral dermatitis exhibits marked erythematous pinpoint papules and pustules that are generally smaller than characteristic rosacea lesions, and are located primarily in the perioral region (while sparing a clear zone around the vermilion border of the lips). Flushing, blushing, and telangiectasia are usually not clinically appreciated with typical perioral dermatitis. Some experts consider this disorder to be a variant of rosacea.10-12
Rosacea vs. Seborrheic Dermatitis
Seborrheic dermatitis is characterized by erythema accompanied by greasy scales, both of which tend to occur in the nasolabial folds, within the ear canals, the retroauricular, scalp, and glabellar region, and eyebrows. The scales and crusts associated with ocular rosacea closely resemble those of seborrheic dermatitis, so the two conditions can be easily confused. The presence of acne or seborrheic dermatitis is not sufficient to rule out a diagnosis of rosacea because rosacea may coexist with either of these conditions.10
Treatment
Effective management of rosacea requires early diagnosis, avoidance of recognized flare factors (tripwires), proper skin care (cleansing regimens and appropriate cosmetic choices), and control of current disease with appropriate pharmacologic (topical and/or systemic) therapy and maintenance of remission with continued topical preparations. Patient education and compliance is critical to achievement of each of these therapeutic goals.
Triggers are both exposures and situations that can cause a flare of the flushing and skin changes in rosacea.6 These may be generally categorized as environmental, chemical, and dietary triggers. An NRS survey revealed that sun exposure is the most common tripwire. Flushing can also be elicited by other trigger factors such as heat, exertion, emotions, weather, food, alcoholic beverages, cosmetics, disease, or certain drugs. Medications that may instigate flushing and potentially aggravate rosacea symptoms include corticosteroids, vasodilators, angiotensin-converting enzyme inhibitors, and niacin.18
Most often, patients present for the first time with mild rosacea and initial therapy is usually topical preparations. Some patients with significant inflammatory rosacea require oral medication in addition to topical medications to induce remission. However, once remission has been achieved, symptoms are usually controlled with appropriate topical medications.15
The topical agents approved for rosacea are listed in the order of their availability in the United States market (see Table: "Topical Agents for the Treatment of Rosacea"). Sulfacetamide and sulfur preparations (gels, creams, lotions, mask, cleansers, emulsions, and cloths) have been shown to be efficacious in patients with rosacea. One of the most recent additions to the sulfacetamide-sulfur armamentarium is a cream formulation inclusive of sun protection factor (SPF) 18 sunscreen (Rosac). Although the mechanism of action is not fully understood, it is thought that the benefit is primarily from the anti-inflammatory properties.19
Currently, there are two first-line topical therapies: metronidazole and azelaic acid. Metronidazole has been widely used since its approval in 1989. Controlled studies have established that the gel, lotion, and cream formulations of metronidazole 0.75% demonstrate equal efficacy. In addition, the 1.0% and 0.75% formulations of metronidazole demonstrate comparable efficacy regardless of once- or twice-daily application.13 The reduction in lesion count for metronidazole ranges from 48% to 65%. Erythema reduction for metronidazole ranges from 36% to 41%. Symptom improvement for metronidazole ranges from 54% to 88%. Topical metronidazole offers efficacy comparable with oral tetracycline 500 to 750 mg per day.20
The metronidazole cream formulation is for patients with dry skin, the gel is recommended for patients with seborrhea (oily skin), and lotion is an optimum choice for patients with combination skin.21 Though the exact mechanism of action is unknown, metronidazole is shown to diminish erythema, reduce inflammatory papules and pustules, and allow for long-term suppressive control.13,20,21
Azelaic acid, a naturally occurring dicarboxylic acid (found in most daily diets) is shown to be efficacious in the treatment of patients with rosacea.22,23 The mechanism of action of azelaic acid in rosacea is unclear, but its effect is believed to be associated with anti-inflammatory and antimicrobial properties. Two multicenter, 12-week, randomized trials showed that azelaic acid had significantly greater efficacy than other vehicles in reducing the number of inflammatory papules and pustules associated with rosacea. Significant treatment effects were seen as early as 4 weeks and progressive improvement was shown thereafter.22-23
In addition, a double-blind, 15-week, randomized trial compared the efficacy of azelaic acid and metronidazole in 251 patients with moderately-severe rosacea. Reduction in the number of inflammatory lesions and improvement in erythema severity was found to be significantly greater in the azelaic acid group.24
Further, the 15% gel formulation has demonstrated greater clearance of inflammatory lesions and erythema than the 20% azelaic acid cream formulations (Azelex). The 15% gel contains a higher percentage of dissolved azelaic acid than the 20% cream. In a Franz flow-through diffusion cell study, azelaic acid gel demonstrated a much higher absorption into skin (25.3%) than the cream formulation (3.4%).25 Thus, the 15% gel formulation is shown to be an effective first-line topical agent in the treatment of rosacea.
Due to its chronic nature, rosacea requires definitive intervention at the beginning of treatment and long-term therapy to maintain remission and reduce severity of flare-ups. Treatment is most effective when it is tailored to the manifestations of the individual patient. Patients who are well-educated about the purpose and goals of treatments are more compliant with suggested therapies. Therefore, it is important to explain the action and purpose of any medication, how and when to take it, and how to watch for and respond to possible adverse effects.26
There is currently no universally accepted algorithm for the treatment of rosacea. Ongoing research is evaluating tailored treatment regimens for patients presenting with specific rosacea subtypes. Though the suggested novel treatment options are promising, they are based primarily on personal clinical observation and small studies. More rigorous controlled studies may illuminate better rosacea treatment choices in the future.
Current treatment options are based on the severity of the disease and patients' expectations of therapy. A popular method of treatment in moderate-to-severe rosacea is combination therapy with an oral antibiotic and a topical medication. The oral medication is used for rapid relief of signs and symptoms, and the topical agent is used for long-term suppression with the plan of tapering off the oral antibiotic.
The oral antibiotics are more effective for inflammatory lesions (papules and pustules) than for erythema and telangiectasia (see Table: "Oral Preparations for the Treatment of Rosacea"). The success of antibiotic therapy is primarily due to the anti-inflammatory effects rather than antimicrobial properties. One approach might be an initial dosage of tetracycline 500 mg twice a day administered for 4 to 6 weeks. As soon as improvement is significant, the antibiotic is decreased to 500 mg once a day for the next 4 to 6 weeks, then 250 mg each day if remission is still appreciated. If the skin remains clear, the oral antibiotic is discontinued. If the patient has a flare at any point, it is recommended to return to the preceding dosage and frequency administration that kept the skin clear.14
If the patient cannot tolerate tetracycline, alternative antibiotics include erythromycin (500 mg twice a day), doxycycline (100 mg daily or twice a day), minocycline (100 mg daily or twice a day), trimethoprim/sulfamethoxazole (one double strength tab daily), and clarithromycin (500 mg twice a day). A few studies have shown that a subantimicrobial dose of doxycycline (Periostat 20 mg twice a day) may be effective for rosacea as well.27,28
Consultation with subspecialists may be required for the management of rhinophyma, ocular complications, or severe disease.29 In severe cases, isotretinoin (Accutane, Amnesteen, Clavaris, Sotret) is utilized. This is a synthetic retinoid that reduces the size of sebaceous glands and alters keratinization. Studies report improvement in inflammatory lesions, edema, and rhinophyma, but little change in erythema. Severe or resistant symptoms can sometimes be controlled at doses 0.2 mg/kg/day to 1.0 mg/kg/day.4,6,16,25,28 The treatment of severe, resistant rosacea with these medications necessitates a referral to a dermatologist for close monitoring and evaluation for a contraceptive plan for female patients, as isotretinoin is a known teratogenic medication. In addition, patients should be evaluated and carefully monitored for evidence of depression.
Surgical interventions include pulse light and laser therapy for telangiectasia and rhinophyma. In severe rhinophyma, cryosurgery, dermabrasion, electrosurgery, carbon dioxide lasers, scalpel shaving, excision, and skin grafting are used to reshape the nose.25
It is important that patients use pharmacotherapeutic agents as directed and that they make lifestyle changes that help to reduce flushing and associated symptoms. For example, patients with rosacea should avoid exposure to sunlight and use a sunscreen in addition to avoiding cosmetics and medications associated with skin irritations. Other lifestyle changes such as avoiding triggers that worsen symptoms should be suggested. Although rosacea cannot be cured, its symptoms can be reduced and its progression managed through appropriate treatment and lifestyle modifications.
Despite the fact that rosacea usually causes limited physical effects, the prominent visibility of these changes often leads to intense psychosocial distress. Therefore prompt diagnosis and accurate treatment is important to improve quality of life. Although the exact cause of rosacea is unknown, its progression, signs, and symptoms can readily be alleviated. In fact, based on a NRS survey, over 70% of rosacea respondents reported that medical treatment had improved their emotional and social well-being.30 Thus, optimal management of rosacea involves a partnership between the informed healthcare provider and a motivated patient.
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