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Systemic Therapy for Rosacea
H. E. Baldwin, MD
Rosacea is a common disorder that is thought to affect 13-14 million people in the US alone.1,2 It is likely that the actual number is substantially higher. Rosacea affects all races, although erythema may be less prevalent in patients with skin types IV and V. The rate of occurrence appears to be higher in women; however, men are more likely to develop phymas. Patients are most often diagnosed with this condition in their 30s-50s.
To truly understand the effects of rosacea on patients, the psychosocial impact must be evaluated along with the visible aspects of this disease. For many of our patients, the stigma of a “drinker’s nose” and the social and professional isolation that can result from low self-esteem is far more significant than the clinical reality.
Contributing to the frustration experienced by patients with rosacea is the fact that as clinicians, we do not truly treat rosacea, but rather manage it. We cannot offer patients cures, simply improvements. As with all chronic conditions, continual therapy inevitably leads to non-adherence. The benefits derived from a combination of both medical and psychological approaches cannot be overemphasized. The overall objective is the improvement of the quality of life of patients, and in 2007, this goal is easier to attain thanks to topical medications that reduce skin irritation. Furthermore, with the advent of safer, once-daily systemic medications, it is possible to liberate patients from the use of topical products.
Classification of Rosacea
Rosacea is a condition characterized by a constellation of symptoms including central facial erythema and telangiectasias, papules and pustules, granulomatous nodules, phyma formation, and ocular changes. The disorder is capricious with flares and remissions occurring without rationale. For the task of discussing therapy, rosacea is best viewed as a collection of several conditions with a common name. Although many patients have polymorphic disease, most have one predominating feature.
The most commonly used classification system is based on predominant lesion morphology and was developed by a committee of the National Rosacea Society and published in 2002.3 Patients are classified as having one of four types of rosacea: erythematotelangiectatic, papulopustular, phymatous, or ocular with a variant form referred to as granulomatous. Individual patients may straddle one or more subtypes, but this system allows us to determine therapy based on similar lesion types. Therapeutic options for the various lesion types are easily categorized and there are few medications or modalities that are significantly effective in more than one category.
Pathophysiology of Rosacea
Our lack of understanding with regard to the pathogenesis of rosacea hampers our therapeutic efforts. Still unclear at this time is the fundamental issue of whether or not the papules and pustules are based in the follicle. There is a growing consensus that bacterial infection does not play a role in rosacea etiology. The neurologic or hormonal mechanisms that may generate the flushing reaction and phyma formation are similarly unknown. It is also unclear if accumulated sun damage, which bears many biochemical and clinical similarities to vascular rosacea, is involved in its pathogenesis.
What is known is that inflammation plays an important role in lesion formation. Inflammatory cells release proinflammatory cytokines and degradative enzymes that induce angiogenesis and damage dermal constituents.4
The outcome of our poor understanding of its pathogenesis is that treatment has been traditionally based on disease endpoints rather than targeting the underlying anomalies. Inflammation is treated with anti-inflammatory agents, flushing with vasoconstrictors, and telangiectasias with laser and light therapy. Until recently, papules and pustules were treated with antibiotics and no target organism.
Oral Therapeutic Options
Oral antibiotics have been used off-label for the treatment of rosacea since the 1950s because it was believed that microorganisms were causative. We now know that there is little to no evidence supporting this premise. Although not curative, the observed benefits of oral antibiotic treatment in patients with rosacea have made clinicians and patients reluctant to exclude these agents from their therapeutic armamentarium, much less to downgrade them from their first-line status.
Due to the chronicity of this disease, antibiotic use is often long-term and can produce side-effects. Furthermore, overuse of antibiotics is associated with the emergence of resistant strains of bacteria that have the potential to result in adverse global health consequences.
Tetracycline received US FDA approval in 1952 and the derivatives doxycycline and minocycline soon followed in 1966 and 1972, respectively. At the time of their introduction, they were known to be bacteriostatic and have broad-spectrum action. Since then, we have come to recognize the anti-inflammatory properties of the tetracycline class of antibiotics.
Tetracyclines are known to down-regulate the production of proinflammatory cytokines such as IL-1 and TNF-alpha.5 They also inhibit neutrophil chemotaxis and the production of nitric oxide, reactive oxygen species, and matrix metalloproteinases (MMP).6,7 This ability of tetracyclines to modulate the inflammatory response pathway, reducing the inflammatory response, is believed to be the rationale for its effectiveness in treating rosacea.5
Tetracyclines are highly effective for papulopustular rosacea, requiring only 3-4 weeks of treatment for substantial improvement. Tetracycline 250-1000mg q.d., doxycycline 100-200mg q.d., and minocycline 100-200mg q.d. are most common. Use of oral tetracyclines until clinical improvement is seen, followed by a transition to topical antibiotics offers an alternative therapeutic regimen. There are patients for whom low-dose, long-term use of antibiotics are necessary to maintain control of their rosacea.
Long-term treatment with antibiotics is problematic for numerous reasons including significant side-effects.8-10 Oral use of tetracyclines can result in disorders such as candidal vulvovaginitis, gastrointestinal distress, and even pseudotumor cerebri. Treatment with doxycycline can result in photosensitivity, and minocycline in vertigo and blue dyspigmentation. Minocycline has also been implicated in the development of lupus-like syndromes and hypersensitivity reactions. Of world-wide importance is the concern regarding emerging antibiotic resistance due to over/ misuse of antibiotics.
Anti-inflammatory dose doxycycline (20mg doxycycline hyclate) was FDA approved in 1998 for the treatment of adult periodontitis. The labeling permits continuous use for up to 12 months, and as such it is the only tetracycline approved for long-term use. It has been shown to be effective in treating papulopustular rosacea with a low incidence of adverse effects. Bikowski treated 50 patients with all types of rosacea and, at 4 weeks, noted an 80%-100% improvement in inflammatory lesions, and a 50% reduction in erythema.10
Although doxycycline has been shown to be highly effective, perhaps its major contribution is that dosage at 20mg results in sub-antimicrobial blood levels. Several studies have reported no effect on antibiotic susceptibility patterns in up to 18 months of continuous therapy and in 9 months post-treatment.12-14
Golub, in 1998, showed that doxycycline hyclate (Periostat®, CollaGenex) had anti-chemotactic activity, was a scavenger of reactive oxygen species and inhibited the enzyme MMP from being released.12 Of primary importance is the ability of doxycycline hyclate to inhibit activation of the MMP-2 and MMP-9 enzymes that break down the capillary vessel basement membrane.
In 2006, a once-daily controlled-release formulation of doxycycline monohydrate became available (Oracea®, CollaGenex Pharmaceuticals). As the first FDA-approved oral treatment for rosacea, the once-daily 40mg capsule combines 30mg immediate-release and 10mg delayed-release doxycycline. The low dose remains below the antibiotic threshold and the controlled release allows for once-daily dosing. Acting as an anti-inflammatory medication rather than an antibiotic, controlled-release doxycycline does not exert selective pressure on microorganisms and as such does not cause bacterial overgrowth (i.e., folliculitis, vaginal candidiasis) or encourage the development of bacterial resistance. Clinical studies have shown the formulation to be both efficacious and safe.15 With once-daily dosing, compliance should also be improved.
Erythromycin is an effective antibiotic in the treatment of papulopustular rosacea, but its use is often limited by GI distress. Erythromycin in doses of 250-1000mg/day is generally used in patients who are intolerant to tetracyclines and in pregnant women in whom tetracyclines are contraindicated.
Second generation macrolides such as clarithromycin and azithromycin have been shown to work faster and with less GI distress than erythromycin.16 One study that followed patients for 3 years showed that subjects taking clarithromycin required less treatment time per year than those taking doxycycline (10.2 weeks/yr vs. 14.6 weeks/yr).17 A 12-week trial of azithromycin in tapering doses showed an 89% reduction in inflammatory lesions.18
The relatively small advantages of the second generation macrolides, however, need to be weighed against the cost differential in the US of a 30-pill supply: erythromycin enteric coated capsules $8.99, clarithromycin $107.49, and azithromycin $214.95.19
In the last decade, there has been increasing concern over the prevalence of antibiotic resistance. Dahl reported the rate of antibiotic-resistant Propionibacterium acnes (P. acnes) is up to 60%.20 Globally, antibiotic-resistant P. acnes increased from 20% to 62% from 1978-1996.21 European studies saw increases of 20% and 50% for tetracycline and erythromycin resistance respectively.22,23 Consequently, there are concerns that increasing P. acnes resistance would result in a reduction in treatment success over time in rosacea patients.
Even greater cause for concern is the ability of P. acnes to transfer resistance to other, more pathogenic bacteria. Levy evaluated the long-term (>6 months) use of antibiotics in 105 acne patients.24 He found that 85% of patients cultured positive for tetracycline resistant Streptococcus pyogenes in the oropharynx compared with 20% in the control group. Margolis, et al. suggested that this was not purely of academic interest, but translated into actual increase in disease.25 In a large, retrospective study, an increase in upper respiratory infections in acne patients treated with either topical or oral antibiotics for greater than 6 weeks was seen. With the recent epidemic of methicillin-resistant Staphylococcus, tetracycline resistance has alarming implications.26,27
Concerns about resistance have resulted in the suggestion by several authors that long-term use of antibiotics be discontinued in acne therapy;21,28,29 and serves as an even more appropriate recommendation in rosacea where there is no evidence of a microbial pathogenesis. Because bacterial resistance is not as much of a concern, the use of anti-inflammatory dose doxycycline and other non-antibiotic alternatives in the treatment of rosacea is preferable whenever clinically appropriate.
Although effective in the treatment of rosacea, metronidazole has been associated with potential (although rare) side-effects such as neuropathy and seizures.30 Alcohol abstinence is required during use to avoid a disulfiram-like reaction and headache.31 Although rarely used in the US, oral metronidazole is prescribed frequently in Europe for long-term therapy of rosacea at doses of 200mg b.i.d.31-34 In a double blind study of patients with papulopustular rosacea, it was shown to be as effective as oral oxytetracycline 250mg b.i.d.35 Pregnancy category B labeling makes it an option for pregnant women.
Isotretinoin is highly effective in the treatment of rosacea. It is one of the few medications that is capable of treating more than one subtype of disease. Onset of action is slower than that seen with the use of oral antibiotics.36,37 In 1981, Nikolowski and Plewig showed that treatment resistant patients taking isotretinoin experienced fewer papules and pustules, a reduction in erythema, and decreased nasal volume.38 Irvine, et al. demonstrated that this drug could halt rhinophyma by diminishing sebaceous gland size and number.39
More studies are needed to determine appropriate dosing schedules as well as optimal treatment duration. Unlike in acne vulgaris, it is not clear that isotretinoin can produce a permanent remission in rosacea. Schmidt and Raff documented remissions lasting up to 2 years after a course of isotretinoin.40 More recently, Erdogan, et al. utilized low-dose isotretinoin at 10mg q.d. for 4 months and showed significant reduction in inflammatory lesions, erythema and telangiectasia at 9 weeks.37
In our continuing search for a therapy that does not result in antibiotic resistance, isotretinoin may be a viable alternative, especially in males and older women past child-bearing years. Low dose (10mg q.d. or q.o.d.), long-term use of isotretinoin can result in minimal risks of side-effects. Birth defects, however, are possible at any dose of this drug; low dose does not mean low vigilance.
Reports in the literature support using dapsone in severe, refractory rosacea.41 It is particularly helpful in patients for whom isotretinoin is contraindicated.
Drugs That Antagonize Flushing
Many anecdotal reports exist regarding the use of agents that antagonize the flushing reaction, including vasoconstricting agents, and drugs that alter flushing reactions in response to emotional stimuli.
Beta blockers in low doses (i.e., nadolol,9 naloxone,42 ondansetron,43 aspirin,44 and numerous selective serotonin reuptake inhibitors19) have been reported in isolated cases to be effective. However, there is no evidence-based research to support their use.
Craige and Cohen recently revisited the use of propranolol in the control of flushing and blushing.45 At starting doses of 10mg t.i.d., none of their nine patients improved. Six of nine patients improved when doses were escalated to 20-30 mg t.i.d. At such high doses, three patients withdrew from the study due to side-effects. This study shows that the perceived ineffectiveness of beta blockers may be due to inadequate dosing.
Clonidine has also been reported to improve flushing and blushing reactions at doses of 0.05mg b.i.d.46 At this dose there was no reduction in blood pressure, but lower baseline malar temperature may have been reduced by peripheral vasoconstriction. Although some patients do remarkably well on clonidine, responders are not clinically identifiable before treatment. Since control of this feature of rosacea is so difficult, a trial course may be indicated.
Therapy Based on Rosacea Subtype
The erythematotelangiectatic subtype of rosacea is the most difficult to treat. There is little evidence that topical or oral antibiotics have any role in the treatment of erythema, telangiectasias and flushing-blushing reactions. Isotretinoin may improve erythema resulting from inflammation, but this effect may be transient. Drugs that antagonize flushing may be helpful in some patients. Vascular laser and light therapy is the most effective modality in this subtype.
The papulopustular type of rosacea is the easiest subtype to treat. Most of these patients respond readily to topical medications such as metronidazole, benzoyl peroxide, clindamycin, erythromycin, and azelaic acid. In several studies, topical medications were shown to be equally effective to oral medications although therapy may take longer to be effective.
Since 2006 there has been a paradigm shift in the therapeutic decision-making process for treating rosacea. In the past, topical agents were considered as first-line therapy, and oral agents were introduced only when topical medications were ineffective, or were used in patients for whom immediate response was paramount. With the advent of once-daily, non-antibiotic dosing of doxycycline, oral therapy has become more commonly prescribed as first-line treatment. Often oral and topical antibiotics are used in combination; the resulting effect may be synergistic. Ultimately the patient may be converted to topical therapy alone for maintenance purposes. However long-term, anti-inflammatory dose doxycycline offers a viable alternative.
Isotretinoin is highly effective in this type of rosacea, especially given that low-dose, long-term therapy is an option particularly in men and women of nonchildbearing potential.
Dapsone may be necessary in refractory rosacea or in a patient for whom isotretinoin is contraindicated.
Surgical or laser ablation is often necessary to eradicate existing lesions of significant size. Isotretinoin has been reported to halt the progression of rhinophymata and to shrink overall volume of phymata by reducing the size of the sebaceous glands, but it does not appear to be curative.37,39,40,47-50
Mild, chronic ocular rosacea responds well to topical agents and eyelid hygiene. More significant disease responds promptly and substantially to virtually any oral antibiotic. Tetracyclines, because of their safety profile, are most often used.51,52 Isotretinoin use may improve the more severe presentations of ocular rosacea, including coloboma formation and corneal erosions. Potential side-effects for this type of rosacea include dry eyes and gritty irritation during therapy.
The granulomatous variant of rosacea is treated in the same manner as papulopustular rosacea reviewed above. Severe disease also responds to the use of oral and intralesional corticosteroids.
Until recently, there had been little change in the systemic treatment options for rosacea over the last several decades. In 2007, more aggressive and innovative uses of existing oral agents have resulted in novel therapeutic approaches. The development of anti-inflammatory dose doxycycline monohydrate is an intriguing alternative to long-term or episodic use of full-dose antibiotics. Once-daily dosing with the controlled-release formulation of doxycycline monohydrate can be expected to improve compliance and therefore efficacy. Furthermore, anti-inflammatory dose doxycycline and isotretinoin are helpful modalities for preventing treatment failures. Agents with good or acceptable safety profiles allow for long-term therapy and provide sustained remission. More importantly, the use of oral agents that do not increase the likelihood of future bacterial resistance is of global importance.
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