Current Therapies for the Management of Patients with Rosacea

Payer Perspectives in Dermatology - Rosacea
Caroline Helwick

For many patients suffering from rosacea, simple interventions can lessen some of the symptoms. Patients should receive instruction on proper skin care, education about potential triggers, and reassurance that with effective management their skin should improve and the most severe form of rosacea—phymatous changes—will be avoided. When these simple strategies are not sufficient, medications are available to target some components of rosacea, although an effective treatment for the skin redness that is associated with rosacea remains an unmet need.

Topical Medications
Topical therapy is often sufficient for mild-to-moderate papulopustular rosacea. The 3 topical agents approved by the US Food and Drug Administration (FDA) for the topical treatment of rosacea include metronidazole (0.75% gel, 1% gel, and 1% cream), benzoyl peroxide (2.5%-10%, multiple formulations), azelaic acid (15% gel or 20% cream), and sodium sulfacetamide 10%/sulfur 5% cream or lotion (an older product with new formulations that may be effective in mild disease). In patients with refractory papulopustular rosacea, tretinoin 0.025% cream or 0.01% gel, with or without topical antibiotics, can be prescribed.1

Metronidazole and azelaic acid are mainstays of treatment. They are believed to work by inhibiting neutrophil functions and by ameliorating the damaging effects of reactive oxygen species.2,3 Metronidazole can be applied once or twice daily, but the once-daily 1% gel formulation can improve compliance, which is important with a chronic condition such as rosacea.4 Azelaic acid cream is considered comparable in efficacy to topical metronidazole.5

Oral Systemic Therapy
Tetracyclines have been the primary treatment of the inflammatory lesions of rosacea for decades in dosages that vary from 40 mg to 500 mg once or twice daily. The second-generation tetracyclines, including doxycycline and minocycline, have improved bioavailability and are better tolerated.6

The standard (ie, antibiotic) doses of the tetracyclines are effective in treating rosacea and are used as maintenance therapy to keep rosacea in check; however, they are not approved by the FDA for this purpose. In addition, concerns have been raised that standard-dose tetracyclines will facilitate antibiotic resistance.1 The use of antibiotics eliminates sensitive strains of bacteria that the patient’s skin harbors, while leaving resistant strains to become even more entrenched and hard to treat.

Rosacea specialists have issued a call to practice good antibiotic stewardship, which is important for preserving the efficacy of antibiotics when they are truly needed.1 Clinicians are being encouraged to avoid using broad-spectrum antibiotics, to limit the duration of antibiotic therapy, to use these drugs only when indicated and in appropriate doses, and to avoid prescribing the most potent antibiotics.1

Low-Dose Antibiotics
Doxycycline 40-mg modified-release capsules (30-mg immediate-release beads, 10-mg delayed-release beads) taken once daily is the first and only oral medication that is FDA approved for the treatment of papulopustular rosacea. This formulation is considered sub-antimicrobial and is referred to as “anti-inflammatory–dose doxycycline” in the peer-reviewed medical literature, because its pharmacokinetic and microbiologic profiles render it less likely to precipitate antibiotic resistance, which is a common concern with oral antibiotics.7-11 The plasma concentrations achieved with this drug provide anti-inflammatory effects that are unrelated to antibiotic activity and are below those required to achieve the minimum inhibitory concentrations needed to suppress bacteria.11 Daily administration of this agent has not been shown to induce antibiotic resistance, even after 9 months of continuous use.1

Once-daily anti-inflammatory–dose doxycycline has proved effective in randomized phase 3 clinical trials and in studies in the community setting.7-11 In a noninferiority trial comparing anti-inflammatory–dose doxycycline to doxycycline 100 mg, the anti-inflammatory dose demonstrated equivalent efficacy to the antimicrobial dose at week 16.8

Anti-inflammatory–dose doxycycline can also be combined with topical agents, which may enhance the efficacy of the treatment, according to studies of patients who used the systemic drug together with metronidazole topical gel 1%, or with topical azelaic acid gel 15%.10,12,13 In an open-label, community-based study of 1421 patients with mild-to-severe papulopustular rosacea, anti-inflammatory–dose doxycycline was prescribed as monotherapy or as an add-on therapy to topical metronidazole, azelaic acid, or to sodium sulfacetamide.9 After 12 weeks, 75% of patients in both arms reported their skin as clear or near clear, as well as significant improvements in their quality of life.9

Facial Erythema in Rosacea an Unmet Need
Inflammatory lesions (papules and pustules) can markedly improve with appropriate topical and oral medications, but the accompanying visible redness of rosacea usually persists at a level that is worrisome to patients.14 In other words, although available medications are effective for treating papulopustular rosacea, they do little to control erythematotelangiectatic rosacea. The FDA-approved agents that are currently used to treat papulopustular rosacea, and others that are used off-label (eg, antibiotic doses of tetracyclines), have been shown to reduce the overall severity of facial erythema; however, this finding relates primarily to a reduction in redness around the lesions, whereas diffuse facial erythema tends to persist.14 The fixed changes in the skin’s vasculature that cause diffuse and persistent redness characteristics of rosacea are not responsive to the mechanism of action of conventional rosacea therapies.14

As James Q. Del Rosso, DO, FAOCD, stated in his recent discussion of the management of rosacea, “The scenario of diffuse and persistent facial erythema…is a common clinical challenge in rosacea-affected patients who are already using recognized medical therapies, and has been described as an ‘unmet need’ in rosacea therapy.”14 Early findings from novel therapies in the drug pipeline suggest that this scenario may soon be addressed.

Physical Modalities for Erythema
Meanwhile, a variety of physical modalities have been used to treat facial erythema and telangiectasias (tiny, visible blood vessels), in particular, laser- and light-based therapies. Published studies have evaluated intense pulsed light, pulsed dye laser, and nonpurpuragenic pulsed dye laser, and, in general, have shown a reduction in facial redness, a decrease in telangiectasias, an improvement in symptoms, and a favorable impact on quality of life.14

Lasers harness wavelengths of powerful light in short bursts (which creates heat) to destroy blood vessels without harming the surrounding tissue. Typically, 3 or more treatments are given in 4- to 6-week intervals. In a 2008 study, the high-energy 595-nm long pulse duration pulsed dye laser was evaluated in 20 patients with rosacea; treatment was delivered to the entire face and to telangiectasias.15 The average rosacea score (on a scale of 0-6) decreased from 2.7 at baseline to 1.4 after treatment.15 In another study, 100% of patients treated with the 532-nm laser reported mild-to-moderate improvement in redness and in telangiectasias.16 A study comparing nonpurpuragenic pulsed dye laser with intense pulsed light found that both significantly reduced redness and telangiectasia in 29 patients with erythematotelangiectatic rosacea who were receiving 3 monthly treatments.17 A more recent prospective study of 20 patients showed a highly significant improvement in quality of life after laser treatment.18 The mean Dermatology Life Quality Index scores were reduced from 17.3 at baseline to 4.3 after laser treatment.18

Intense pulsed light is similar to laser, but it generates a broader spectrum of light to treat a wider spectrum of tissue.19 Other lasers used to treat telangiectasias include the KTP laser, diode laser, and Nd:YAG laser, but studies suggest that they may not be as effective as the pulsed dye laser.20 The Nd:YAG and CO2 lasers are useful in improving phymatous changes of the nose.19

Laser and light therapies, however, are not cures for rosacea and additional treatments are often needed, because blood vessels recur. Realistic expectations are essential, and, for some patients, these approaches worsen rosacea. Furthermore, laser and light therapies are also not typically covered by insurance. Individual sessions can cost approximately $300 to $600, and several treatment sessions are required to achieve the best results.20 Therefore, light and laser treatments may be unavailable to many patients.

Conclusion
Simple interventions can improve rosacea in many patients. Topical medications can be effective in improving pimples and pustules, and, for more challenging cases, anti-inflammatory–dose doxycycline and light-based therapies are helpful. However, the erythematous component of rosacea—the redness of the skin—is typically not improved by the current treatment modalities, and this remains an unmet need. Drugs that are in development have been designed to address this component of rosacea.

References

  1. Baldwin HE. Diagnosis and treatment of rosacea: state of the art. J Drugs Dermatol. 2012;11:725-730.
  2. Akamatsu H, Oguchi M, Nishijima S, et al. The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: a possible mechanism of action of metronidazole in rosacea and acne. Arch Dermatol Res. 1990;282:449-454.
  3. Akamatsu H, Komura J, Asada Y, et al. Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res. 1991;283:162-166.
  4. Dahl MV, Jarratt M, Kaplan D, et al. Once daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea. J Am Acad Dermatol. 2001;45:723-730.
  5. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999;40(6 pt 1):961-965.
  6. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51:499-512;quiz 513-514.
  7. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56:791-802.
  8. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.
  9. Baldwin HE. A community-based study of the effectiveness of doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads) on quality of life and satisfaction with treatment in participants with rosacea. Cutis. 2010;86(5 suppl):26-36.
  10. Del Rosso JQ. Effectiveness and safety of doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads) once daily as add-on therapy to existing topical regimens for the treatment of papulopustular rosacea: results from a community-based trial. Cutis. 2010;86(5 suppl):16-25.
  11. Webster GF. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). Cutis. 2010;86(5 suppl):7-15.
  12. Del Rosso JQ, Bruce S, Jarratt M, et al. Efficacy of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg versus metronidazole gel 1% plus oral doxycycline 40 mg in mild-to-moderate papulopustular rosacea. J Drugs Dermatol. 2010;9:607-613.
  13. Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645.
  14. Del Rosso JQ. Advances in understanding and managing rosacea: part 2: the central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea. J Clin Aesthet Dermatol. 2012;5:26-36.
  15. Bernstein EF, Kligman A. Rosacea treatment using the new-generation, high-energy, 595 nm, long pulse-duration pulsed-dye laser. Lasers Surg Med. 2008;40:233-239.
  16. Maxwell EL, Ellis DA, Manis H. Acne rosacea: effectiveness of 532 nm laser on the cosmetic appearance of the skin. J Otolaryngol Head Neck Surg. 2010;39:292-296.
  17. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009;35:920-928.
  18. Shim TN, Abdullah A. The effect of pulsed dye laser on the dermatology life quality index in erythematotelangiectatic rosacea patients: an assessment. J Clin Aesthet Dermatol. 2013;6:30-32.
  19. National Rosacea Society. Lasers offer key treatment options for more difficult signs of rosacea. Rosacea Rev. Summer 2005. www.rosacea.org/rr/2005/summer/article_1.php. Accessed June 26, 2013.
  20. American Academy of Dermatology. Is laser treatment right for your rosacea? www.skincarephysicians.com/rosaceanet/laser_treatment.html. Accessed June 26, 2013.
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Last modified: September 4, 2013
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