Hilary Baldwin, MD
Department of Dermatology, State University of New York, Brooklyn, NY, USA

The Disease

Rosacea is a common condition that is prevalent worldwide. Its incidence is said to be higher in fair-skinned patients, however it is also seen in Asians and African-Americans. Rosacea occurs in both men and women most often after the age of 30 years. It is characterized by the presence of one or more of the following:

  • Central facial erythema and telangiectasias
  • Papules and pustules
  • Granulomatous nodules
  • Phyma formation
  • Ocular changes

Known triggers include UV exposure alcohol intake, spicy foods, and changes in temperature. However, sometimes flares and remissions occur with no rationale.

Classification

A National Rosacea Society committee has classified rosacea into four types based on predominant lesion morphology:

Erythematotelangiectatic

  • Flushing and persistent central facial erythema with telangiectasias. Central facial edema, stinging and burning of the skin, as well as dryness occurs.
  • Most difficult subtype to treat
    • Topical and oral therapy largely ineffective
    • Laser and light therapy most effective

Papulopustular

  • Papules and pustules often seen with persistent facial erythema.
  • Easiest subtype to treat
    • May respond to topical therapy
    • Oral agents more effective. May be used as first-line therapy, when topicals are ineffective or when it is important to speed up the response time.

Phymatous

  • Thickening of the skin, often presenting as rhinophyma
  • Irregular surface nodules, enlarged follicles and sebaceous appearance.
  • The chin, forehead, cheeks, and ears may be involved.
  • Isotretinoin can halt progression and shrink volume, but willnot eradicate completely.
  • Surgical/laser ablation necessary to eradicate existing lesions.

Ocular

  • Sensation of burning, grittiness, dryness, “foreign body sensation”, telangectasia of the sclera. Often, blepharitis, conjunctivitis, chalazions, styes present. Rarely, corneal manifestations (keratitis, infiltrates, and ulcers) may occur.
  • May respond to topical agents and eyelid hygiene.
  • Oral antibiotics readily resolve ocular rosacea.
  • May remit after discontinuation.

This system allows therapy evaluation based on similar lesion types; there are few medications or therapies that are significantly effective in more than one category.2

Pathophysiology

Inflammation plays an important role in lesion formation, however the etiology of rosacea is not well understood. It is generally believed that there is no microorganism involved in
the pathogenesis of rosacea.

Common denominators are believed to include inflammation and degradation of the dermal connective tissue; angiogenesis caused by the upregulation of proinflammatory cytokines; neutrophil chemotaxis; and the production of nitric oxide, reactive oxygen species, and matrix metalloproteinases.

In the face of an absence of a defined pathogenesis, treatment has traditionally been based on disease endpoints rather than targeting the underlying problems:

  • Inflammation is treated with anti-inflammatory agents.
  • Flushing is treated with vasoconstrictors.
  • Telangiectasias are treated with vascular lasers.
  • Pustules are treated with antibiotics without a target organism.

Vasoconstricting Agents

A number of agents have been reported anecdotally to reduce flushing including beta blockers in low doses,3 naloxone,4 ondansetron,5 aspirin,6 and serotonin reuptake inhibitors.7 Clonidine, at 0.05mg b.i.d., has also been reported to be effective for reducing flushing.8 While this suboptimal dose does not reduce blood pressure, it does lower baseline malar temperature by peripheral vasoconstriction.

Antibiotics

Oral antibiotics have been used off-label since the 1950s, but until May of 2006 none had been approved for treating this condition. Antibiotics are highly effective in papulopustular rosacea. However, justification for their use must be based on the recognition that there is little or no evidence demonstrating that rosacea is the result of a bacterial infection, and that reports of antibiotic resistance have been increasing over the past 10 years.

Tetracyclines

Because tetracyclines act to reduce inflammation, they are very effective for papulopustular acne and rosacea with substantial improvement seen after 3–4 weeks. However, relapses often occur after discontinuation.9 Tetracycline 250–1000mg q.d., doxycycline 100–200mg q.d., and minocycline 100–200mg q.d. are most commonly used. Using oral tetracyclines until clinical improvement is seen, then tapering to topical antibiotics, offers a way to maintain control and minimize relapses. However, we should not ignore the lessons learned from the use of long-term oral antibiotics and the resultant potential for bacterial resistance that have developed while treating other skin diseases.

Anti-inflammatory Dose Doxycycline – A New Treatment Option

The reason why tetracyclines are so effective for treating rosacea is likely due to their anti-inflammatory properties, not their role as antibiotics. In May 2006, the FDA approved the first oral prescription therapy for the treatment of inflammatory lesions
(papules and pustules) of rosacea in adult patients. This product, doxycycline (Oracea™), is a once daily 40mg capsule containing 30mg immediate-release and 10mg delayed-release beads. It allows for blood levels of doxycycline to stay within a narrow window: high enough to act as an anti-inflammatory medication, but well beneath the antimicrobial threshold. In two Phase III, double-blind, placebo-controlled clinical trials, patients receiving this drug experienced a 61% and 46% mean reduction in inflammatory lesions compared with 29% and 20%, respectively for placebo (p < 0.001 for each study).10 Side-effects were similar to placebo. Most notably, since the low dose exerts no selection pressure on bacteria, there were no yeast infections reported and continued use did not result in antibacterial resistance.

Erythromycin

Erythromycin is effective for treating papulopustular rosacea, but patients often complain of GI side-effects. Second generation macrolides have been shown to be more effective than erythromycin. However, resistance has been noted in patients in whom an infectious etiology cannot be demonstrated.

Metronidazole

Oral metronidazole, 200mg b.i.d., is often used for long-term treatment of rosacea in Europe.11,12 In a double-blind study, this drug was shown to be as effective as oxytetracycline 250mg. b.i.d.12 Side-effects include rare neuropathy and seizures. Alcohol abstinence is required during use.2

Isotretinoin

Isotretinoin is less commonly used for the treatment of rosacea than it is for acne vulgaris. By reducing the size and number of sebaceous glands, treatment-resistant rosacea patients who were given this drug had fewer papules and pustules, a decrease in erythema, and a reduction in nasal volume in rhinophyma.13,14 Unlike acne therapy where isotretinoin is generally curative, improvement in rosacea is often not as long-lasting. Erdogan, et al. used a low dose of 10mg daily for 4 months with a significant reduction in inflammatory lesions, erythema and telangiectasia at 9 weeks.15 Long-term, low-dose therapy is highly effective in controlling papulopustular rosacea. Use of isotretinoin in adult females of child-bearing potential requires birth control monitoring and extensive counseling because of its teratogenic properties. Distribution of isotretinoin is restricted by a special computer-based risk management program approved by the FDA, designed to further the public health goal to eliminate fetal exposure to isotretinoin. For more information see www.ipledgeprogram.com

Conclusion

Novel uses of old medications and new formulations of systemic medications have broadened the therapeutic armamentarium for treating rosacea patients. It is of primary importance to offer patients safe and effective therapies for this chronic and incurable condition, improving both the clinical and psychosocial consequences of rosacea.

Editor’s Commentary

As Dr. Baldwin points out, there is increasing concern in the medical community about prolonged ingestion of oral antibiotics due to bacterial resistance patterns. This concern has been further validated by the recent elucidation of the complete genome of P. acnes and the finding that this organism possesses inherent mechanisms enabling it to transfer a variety of resistance genes to other microbial species.1,2 Thus, while oral antibiotics have long been the mainstay of rosacea therapy, apprehension about microbiological consequences has tempered enthusiasm for this type of treatment. Complete alcohol avoidance required of those receiving oral metronidazole, and the myriad of potential adverse events associated with isotretinoin have likewise made these alternate agents difficult to administer.

Prior investigation of very low-dose doxycycline suggested efficacy for rosacea.3 Thus, the recent FDA approval and commercial release of a subantimicrobial and purely antiinflammatory dose of this drug in a convenient once-daily formulation might, indeed, have several advantages, i.e. no development of resistance and fewer or no problems with yeast infections. However, comparative clinical trials to demonstrate such advantages have not been done. The goal of such therapy is to administer an antibiotic moiety in a dosage formulation that preserves anti-inflammatory properties but eliminates antiinfective properties, thereby avoiding ecologic pressure on bacteria to become resistant. The exact mechanism(s) by which anti-inflammatory doxycycline improves rosacea is uncertain. Suppression of cytokine and chemokine elaboration, inhibition of matrix metalloproteinases, decreased vasodilatation and other properties have been described.4 This formulation is also notable for its lack of photosensitivity, and for the minimal risk of secondary candidiasis and troublesome side-effects traditionally associated with the tetracycline family.

Another promising oral therapy for rosacea involves the use of an oral blend of nicotinamide and zinc (Nic/Zn).5 The formulation tested contained nicotinamide 750mg and zinc 25mg as active ingredients, along with small amounts of copper and folic acid.
Nearly 80% of subjects reported a patient global evaluation of “moderately” or “much” better when compared with baseline after 8 weeks. Similar to anti-inflammatory dose doxycycline, the precise mechanism of action is uncertain, but suppression of vascular permeability, reduced accumulation of inflammatory cells, depressed mast cell degranulation, and stabilization of lysosomes have all been implicated.6 If larger scale and longer duration studies verify the aforementioned data, then Nic/Zn may further expand our oral therapeutic options.

Rosacea patients often exhibit “irritable” skin, which may be hyper-reactive to a host of topical medications as well as to overthe- counter skin care products.7 Oral therapy may be mandatory for such individuals, and transitioning to topical maintenance should be deferred until significant improvement occurs.

References

  1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 46(4):584-7 (2002 Apr).
  2. Baldwin HE. Oral therapy for rosacea. J Drugs Dermatol 5(1):16-21 (2006 Jan).
  3. Rebora A. The management of rosacea. Am J Clin Dermatol 3(7):489-96 (2002).
  4. Bernstein J, Soltani K. Alcohol-induced rosacea flushing blocked by naloxone. Br J Dermatol 107(1):59-61 (1982 Jul).
  5. Wollina U. The response of erythematous rosacea to ondansetron. Br J Dermatol 140(3):561-2 (1999 Mar).
  6. Bikowski JB, Goldman MP. Rosacea: where are we now? J Drugs Dermatol 3(3):251-61 (2004 May-Jun).
  7. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad. Dermatol 51(4):499-512 (2004 Oct).
  8. Wilkin JK. Effect of subdepressor clonidine on flushing reactions in rosacea. Change in malar thermal circulation index during provoked flushing reactions. Arch Dermatol 119(3):211-4 (1983 Mar).
  9. Sneddon I. A clinical trail of tetracycline in rosacea. Br J Dermatol 78(12):649-52 (1966 Dec).
  10. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust 169(5):259-61 (1998 Sep).
  11. Ross J, Snelling A, Carnegie E, et al. Antibiotic resistant acne: lessons from Europe. Br J Dermatol 148(3):467-78 (2003 Mar).
  12. Espersen F. Resistance to antibiotics used in dermatological practice. Br J Dermatol 139 Suppl 53:4-8 (1998 Dec).
  13. Data on file, CollaGenex Pharmaceuticals.
  14. Pye RJ, Burton JL. Treatment of rosacea by metronidazole. Lancet 1(7971):1211-2 (1976 Jun 5).
  15. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Clin Pharmacol 102(4):443-5 (1980 Apr).
  16. Nikolowski J, Plewig G. [Oral treatment of rosacea with 13-cis-retinoic acid]. Hautarzt 32(11):575-84 (1981 Nov).
  17. Schmidt JB, Gebhart W, Raff M, Spona J. 13-cis-retinoic acid in rosacea. Clinical and laboratory findings. Acta Derm Venereol 64(1):15-21 (1984).
  18. Erdogan FG, Yurtsever P, Aksoy D, Eskioglu F. Efficacy of low-dose isotretinoin in patients with treatment-resistant rosacea. Arch Dermatol 134(7):884-5 (1998 Jul).

Editorial References

  1. Bruggemann H, Henne A, Hoster F, et al. The complete genome sequence of Propionibacterium acnes, a commensal of human skin. Science 305(5684):671-3 (2004 Jul 30).
  2. Bruggemann H. Insights in the pathogenic potential of Propionibacterium acnes from its complete genome. Semin Cutan Med Surg 24(2):67-72 (2005 Jun).
  3. Berman B, Zell D. Subantimicrobial dose doxycycline: a unique treatment for rosacea. Cutis 75(4 Suppl):19-24 (2005 Apr).
  4. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 54(2):258-65 (2006 Feb).
  5. Niren NM, Torok HM. The Nicomide Improvement in Clinical Outcomes Study (NICOS): results of an 8-week trial. Cutis 77(1 Suppl):17-28 (2006 Jan).
  6. Fivenson DP. The mechanisms of action of nicotinamide and zinc in inflammatory skin disease. Cutis 77(1 Suppl):5-10 (2006 Jan).
  7. Draelos ZD. Assessment of skin barrier function in rosacea patients with a novel 1% metronidazole gel. J Drugs Dermatol 4(5):557-62 (2005 Sep-Oct).
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