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Topical Management of Rosacea

Melinda Gooderham, MSc, MD, FRCPC

Peterborough, ON, Canada

Introduction

Many options exist for the treatment of rosacea, including topical and systemic therapy, laser and light-based therapies, and surgical procedures. A classification system for rosacea identifies four subtypes, which may help guide therapeutic decision-making. Standard topical treatment agents include metronidazole, azelaic acid, and sulfacetamide-sulfur. Second-line therapies include benzoyl peroxide, clindamycin, calcineurin inhibitors, and permethrin. Rosacea can contribute to lower self-esteem and have significant psychosocial implications, such as stress at work and social isolation. This can have a significant impact on quality of life and should be taken into consideration when treating these patients.

Prevalence

  • Rosacea is a common chronic skin disorder that is thought to affect approximately 14% of women and 6% of men.1
  • All ethnicities can be affected, but rosacea is most prevalent in fair-skin individuals of northwest European descent.
  • Initial diagnosis most frequently occurs between the ages of 30-50 years.
  • Although rosacea prevalence is higher in women, there is a much greater incidence of severe telangiectasias and rhinophyma (red, bulbous nose) in men, especially in patients presenting with advanced disease.

Diagnostic Features

Rosacea is a chronic relapsing inflammatory skin disorder characterized by facial flushing, persistent erythema, telangiectasia (dilated superficial blood vessels), and inflammatory papules and pustules affecting the central face (across the cheeks, nose, or forehead). The ears, scalp, neck, and chest are less commonly involved.

The National Rosacea Society has described a classification system based on four main subtypes and one variant.2

Subtype 1: Erythematotelangiectatic

  • Characterized by flushing, persistent central facial erythema, and telangiectasia of the cheeks and around the nose.
  • Central facial edema, stinging, burning, pruritus, and roughness, scaling, and a history of flushing alone are also common.

Subtype 2: Papulopustular

  • Characterized by persistent central facial erythema with transient papules or pustules or both.
  • Papules and pustules can also occur in the perioral, perinasal, or periocular regions.
  • There is a resemblance to acne vulgaris, except that comedones (whiteheads and blackheads) are absent, hence, the term “acne rosacea” is sometimes used.
  • Rosacea and acne can coexist, therefore, patients can present simultaneously with comedones, papules and/or pustules.
  • This subtype has often been seen after or in combination with subtype 1.
  • Burning and stinging sensations may be reported by patients; telangiectasias may be present, but obscured by persistent erythema, papules, or pustules.

Subtype 3: Phymatous

  • Common features include thickening skin, irregular surface nodularities, and enlargement.
  • Phymatous rosacea most commonly affects the nose (rhinophyma), but the chin, forehead, cheeks, and ears can also be involved.
  • This subtype frequently occurs after or in combination with subtypes 1 or 2.
  • Patients may also exhibit persistent erythema, telangiectases, papules, and/or pustules.

Subtype 4: Ocular

  • Diagnosis of this subtype is considered when a patient exhibits or reports one or more of the following symptoms: watery or bloodshot appearance, foreign body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectasia, or lid and periocular erythema.
  • Recurrent staphylococcal infection manifesting as styes are common.
  • Patients can experience impaired vision, requiring ophthalmologic consultation.
  • Most frequently, signs and symptoms of ocular rosacea present concurrently with those affecting the skin.
  • Ocular signs and symptoms may precede cutaneous manifestations and vice versa.

One Variant: Granulomatous

  • This is a rare variation of rosacea that is characterized by hard papules or nodules ranging in colour from yellow, brown, or red.
  • The lesions exhibit less inflammation and are typically found on relatively normal-appearing skin of the cheeks and periorificial areas.

Treatment Overview

Treatment starts with making a proper diagnosis, including subtyping. Following this, conservative measures such as trigger avoidance, proper skin care, camouflaging cosmetics, and photoprotection should be discussed in detail with patients. The goals of therapy include the reduction of papules, pustules, erythema, physical discomfort, and an improvement in quality of life. Topical pharmacotherapeutic options include azelaic acid, metronidazole, sulfacetamide 10% + sulfur 5%, clindamycin 1% + benzoyl peroxide 5% gel, clindamycin, and erythromycin. For patients with moderate to severe papulopustular rosacea or those with ocular involvement, systemic therapy is often prescribed - therapeutic options include tetracycline, minocycline, doxycycline, erythromycin, metronidazole, or in severe cases, low dose isotretinoin. The telangiectatic component does not respond to either oral or topical medications, and is best treated with laser and light-based therapies. Surgical intervention may be required for the phymatous subtype. Therapeutic choices will depend on patient expectations, tolerance, previous therapies used, rosacea subtype, and severity.

Azelaic Acid

Azelaic acid (AzA) is a newer therapeutic option that is available for the treatment of rosacea. Although it received regulatory approval in Canada in 2004, AzA has only recently become commercially available in June 2010. AzA is a naturally occurring dicarboxylic acid that can be found in dietary sources, such as whole grains.3 It lacks toxicity, is non-teratogenic and non-mutagenic.4 It has multiple biologic effects including anti-inflammatory, anti-keratinizing, and anti-bacterial activities. The likely mechanism of action in the treatment of rosacea is via inhibition of reactive oxygen species produced by neutrophils.4

  • A novel 15% gel formulation is available for the treatment of rosacea. A 20% cream formulation is approved in the U.S. for acne vulgaris, but it is not currently available in Canada.
  • The 15% gel, although formulated to a lower concentration than the cream, is significantly more bioavailable than the cream because of an optimized aqueous gel vehicle.

Multiple reviews have been published examining the use of AzA in rosacea.3,5,6

  • Two pivotal phase III trials have shown that AzA 15% gel applied twice daily for 12 weeks was superior when compared with the vehicle in the treatment of papulopustular rosacea.7
    • In these studies, a mean reduction in inflammatory lesion counts and improvements in erythema scores were observed in AzA-treated group vs. placebo.7
  • A 15-week study, comparing the twice daily use of AzA 15% gel to metronidazole 0.75% gel also showed a significant benefit for AzA over metronidazole.8

Metronidazole

Metronidazole has been the mainstay of topical rosacea treatment. It is a nitroimidazole antibiotic whose mechanism of action in rosacea is not well established, but it appears to work through an anti-inflammatory mechanism.12,13 Metronidazole is the most widely used topical agent for rosacea.

  • Available as a 0.75% gel, lotion, and cream for twice daily use, and a 1% cream and gel for once daily use.
  • Once daily dosing of 1% metronidazole cream appears to be as effective as twice daily dosing.14
  • It is generally well tolerated and has a low incidence of adverse effects.12,13
  • A recent systematic review of 9 trials demonstrated the efficacy of topical metronidazole vs. placebo.5,15 Most of these studies used 0.75% metronidazole and ranged from 8-9 weeks in duration with one trial lasting 6 months.
    • A reduction in inflammatory lesions and erythema scores were noted, as was an improvement in physician’s global evaluation and patient-assessed measures when these were available.5,15
    • No benefits were noted for telangiectasia in these studies, however, a study by Tan et al. showed improvement in telangiectasiae scores as well as erythema and inflammatory lesion counts using a 1% metronidazole cream with a sun protection factor (SPF) of 15.16
  • Although data is limited, two studies have demonstrated that topical metronidazole may be as effective as oral tetracycline in reducing the inflammatory component of rosacea.17,18
  • The efficacy of topical metronidazole is constant regardless of the formulation, strength, and frequency of application.12
  • Metronidazole also plays a role in maintenance therapy for rosacea, either with or without prior concomitant systemic antibiotic treatment.12
  • Given its high efficacy and tolerability, it will continue to play an important role in the management of rosacea.

Sodium Sulfacetamide + Sulfur

  • An older treatment that has gained new popularity is sodium sulfacetamide 10% + sulfur 5%, which is used to treat acne, rosacea, and seborrheic dermatitis.13
  • It is available in multiple formulations as a lotion, cream, gel, or cleanser.9,13
  • The mechanism of action is not well understood, but the sulfacetamide has anti-bacterial properties, and the sulfur component confers anti-fungal, anti-demodectic, and keratolytic effects.

Other Therapies

  • Many other topical treatments have been reported and are being used for rosacea. Some are effective, but are not yet approved for use in rosacea. Further investigation is needed to determine their role in the topical armamentarium of rosacea therapy.
  • Combination clindamycin 1% + benzoyl peroxide 5% gel, which is approved for use in acne vulgaris, has shown promise in the treatment of rosacea. A double-blind, randomized controlled trial using this formulation once daily showed a significant reduction in inflammatory lesion count, erythema severity, and overall rosacea severity. The treatment was well tolerated.19
  • Topical antibiotics (e.g., clindamycin lotion or cream) have shown benefit in the topical treatment of rosacea, but evidence supporting its use is lacking.
  • The calcineurin inhibitors, tacrolimus and pimecrolimus, have been investigated for use in papulopustular rosacea because of their anti-inflammatory effects. Early reports indicate improvement from tacrolimus in the treatment of steroid-induced rosacea.20 However, while three studies have demonstrated a reduction in erythema associated with rosacea, neither tacrolimus nor pimecrolimus had any benefit over vehicle with respect to lesion counts.21-23
  • Topical retinoids have also been used to treat rosacea, but the true efficacy has not been established. Their use is limited by their irritant potential, and investigators suggested that better tolerated agents, such as adapalene, could be considered.13
  • Topical steroids are sometimes used on a short-term basis for the severe inflammatory component, but long-term side-effects and exacerbating potential limit their use in this chronic condition.13
  • Permethrin 5% cream, which is proposed to work because of its anti-parasitic effects, may target Demodex mites, a potential cause of rosacea.13

Self-Care Tips

Cleansers

  • Due to hypersensitivity of the skin, limit face washing to twice daily. Cleansing can offer a cooling effect that temporarily relieves sensations of burning and itching.
  • Select gentle, mild skin cleansers with non-sensitizing ingredients (i.e., free of fragrances and preservatives).
  • Avoid the use of washing implements (e.g., sponge, brush, wash cloth), especially those with a rough surface that can further aggravate the skin.
  • Allow skin to dry before applying either a moisturizer or medication.

Moisturizers

  • The regimented use of a suitable moisturizer is essential for managing rosacea. If left untreated, dry skin can cause further discomfort, resulting in burning, tightness, itching, and stinging.
  • Recommendations cannot be generalized, since each person with rosacea can react differently to the same product. Water-based moisturizers may be less likely to induce sensitivity reactions.
  • Seborrheic dermatitis is a common concurrent skin condition, appearing as a red and scaly rash on the scalp, eyelids, eyebrows, sides of the nose, and behind the ears. Patients with rosacea can have dry scaly skin secondary to the dermatitis, so no amount of moisturizing will help the scaling until the inflammation is first controlled by medication.

Sunscreens

  • The sun is one of the most common triggers of rosacea flare-ups, therefore, selecting a suitable non-oily broad spectrum sunscreen with SPF of at least 15 to 30 is recommended.
  • The most effective protection against UV radiation is sun avoidance, e.g., by limiting exposure, or at least direct exposure during peak times, and by wearing appropriate clothing and hats.
  • Maintaining proper sun protection is essential, because the heat of the sun and UV exposure can aggravate the skin and result in increased redness and long-term damage to blood vessels.

Cosmetic Camouflage

  • Makeup can be a useful cosmetic tool to conceal the symptoms of rosacea.
  • Foundations or concealers with a green tint are helpful for camouflaging redness, blood vessels, and blemishes.
  • Avoid powder formulations on dry, flaky skin, as these products can collect in areas of dryness and worsen the appearance of skin.

Conclusion

Because of its chronic, inflammatory nature, rosacea requires continuous management. Treatment can be tailored to the subtype and may involve a combination of therapies. Patients should first be counseled on the triggers of rosacea, proper skin care, photoprotection, and camouflaging cosmetic options. Topical therapy is usually first-line, but in moderate-to-severe cases, or those with ocular involvement, systemic therapy may be required. Laser or light-based treatments and surgical procedures can offer added benefit. Many topical agents are available for the treatment of rosacea, and the erythematotelangiectatic and papulopustular variants usually respond most favourably. The Cochrane Collaboration Review of interventions for rosacea concludes there is good evidence that topical azelaic acid and metronidazole are both safe and effective treatments. Other treatment options also include sulfacetamide 10%-sulfur 5%, benzoyl peroxide 5%-clindamycin 1%, or clindamycin alone.

References

  1. Berg M, et al. Acta Derm Venereol 69(5):419-23 (1989).
  2. Wilkin J, et al. J Am Acad Dermatol 46(4):584-7 (2002).
  3. Gupta AK, et al. Int J Dermatol 46(5):533-8 (2007).
  4. Breathnach AS. Medial Hypothesis 52(3):221-6 (1999).
  5. van Zuuren EJ, et al. J Am Acad Dermatol 56(1):107-15 (2007).
  6. Liu RH, et al. Arch Dermatol 142(8):1047-52 (2006).
  7. Thiboutot D, et al. J Am Acad Dermatol 48(6):836-45 (2003).
  8. Elewski BE, et al. Arch Dermatol 139(11):1444-50 (2003).
  9. Bikowski JB, et al. J Drugs Dermatol 3(3):251-61 (2004).
  10. Maddin S. J Am Acad Dermatol 40(6 Pt 1):961-5 (1999).
  11. Thiboutot DM, et al. J Drugs Dermatol 7(6):541-6 (2008).
  12. McLellan KJ, et al. Am J Clin Dermatol 1(3):191-9 (2000).
  13. Nally JB, et al. J Drugs Dermatol 5(1):23-6 (2006).
  14. Jorizzo JL, et al. J Am Acad Dermatol 39(3):502-4 (1998).
  15. van Zuuren EJ, et al. Cochrane Database Syst Rev (3):CD003262. DOI:10.1002/14651858.CD003262.pub3 (2005).
  16. Tan JKL, et al. J Cutan Med Surg 6(6):529-534 (2002).
  17. Nielsen PG. Br J Dermatol 109(1):63-5 (1983).
  18. Veien NK, et al. Cutis 38(3):209-10 (1986).
  19. Breneman D, et al. Int J Dermatol 43(5):381-7 (2004).
  20. Goldman D. J Am Acad Dermatol 44(6):995-8 (2001).
  21. Bamford J, et al. J Am Acad Dermatol 50(1):107-8 (2004).
  22. Karabulut AA, et al. J Eur Acad Dermatol Venereol 22(6):729-34 (2008).
  23. Weissenbacher S, et al. Br J Dermatol 156(4):728-32 (2007).

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