CONTINUING MEDICAL EDUCATION
`
`Rosacea: II. Therapy
`
`Michelle T. Pelle, MD,“ Glen H. Crawford, MD,‘1 and William D. James, MDb
`Boston, Massachusetts, and Philadelphia, Pennsylvania
`'
`
`3 Despite an incomplete understanding of the pathogenesis of rosacea, therapeutic modalities continue to
`expand. The principal subtypes of rosacea include erythematotelangiectatic rosacea, papulopustular
`rosacea, phymatous rosacea, and ocular rosacea. These phenotypic expressions are probablynaused by
`divergent pathogenic factors and consequently respond to different therapeutic regimens. A subtype—
`directed approach to therapy is discussed. in part II of this review. We provide an overview of the available
`topical, oral, laser, and light therapies in the context of these cutaneous subtypes, review the evidence that
`supports their use, and outline their therapeutic approach. Suggestions for future areas of study also are
`provided. (I Am Acad Dermatol 2004;51:499-512.)
`
`Learning objective: At the completion of this learning activity, participants should be familiar with the
`subtype—directed approach to therapy for rosacea including available topical, oral, laser, and light therapies.
`
`to initiating therapy, a dermatologist
`rior
`. 1 should assist patients in identifying factors
`that trigger their signs and symptoms. Trigger
`factors are specific for each patient, and common
`triggers do not affect every patient. They include hot
`or cold temperature, wind, hot drinks, exercise, spicy
`food, alcohol, emotions, topical products that irritate
`the skin or impair barrier function, menopausal
`flushing, and medications that promote flushing.
`Those factors that induce flushing should be avoided
`if feasible. Other key aspects of prevention include
`the daily use of a broad—spectrum, gentle sunscreen,
`avoidance of midday sun, seeking shade, and the use
`of protective Clothing. The signs and symptoms of
`rosacea may be camouflaged with nonirritating cos-
`metics and concealers.
`
`SUNSCREEN
`
`Practicing sun avoidance behaviors is of central
`importance to rosacea management.
`In addition,
`a broad—spectrum sunscreen should be applied daily.
`The physical blockers titanium dioxide and zinc
`oxide are well tolerated by most patients. General
`guidelines for the use of sunscreens by persons with
`rosacea are provided.
`in Table 1. Several rosacea
`creams contain sunscreen ingredients. A combina—
`tion sunscreen and 1% metronidazole is now
`
`From the Department of Dermatology, Boston University Medical
`Centerf‘ and the Department of Dermatology, University of
`Pennsylvania Medical Center.b
`Funding sources: None.
`Conflict of interest: None identified.
`Reprints not available from the authors.
`0190—9622/$30.00
`© 2004 by the American Academy of Dermatology, Inc.
`doi:10.lOl6/j.jaad.2004.03.033
`
`marketed in Canada as Rosasol cream (Stiefel
`Canada,- Inc, Montreal, Quebec).1 Unfortunately,
`some sunscreens can trigger cutaneous irritation
`and produce erythema. Protective ingredients such
`as silicones should be included in sunscreen prep-
`arations to minimize stinging and erythema.
`In
`the form of dimethicone or cyclomethicone,
`sil~
`icones are nonirritating and nonacnegenic occlu—
`sive agents that retard transepidermal water loss,
`impart water—resistant properties to cosmetics, and
`enable them to spread easily over the skin.2 Rosac
`cream (Stiefel Laboratories, Inc, Coral Gables, FL),
`a combination of sodium sulfacetamide 10% and
`
`sulfur 5%, Parsol 1789, and other sunscreens in
`a dimethicone vehicle,
`is now available in the
`United States.
`
`Nichols et al studied the irritant potential of
`various chemical sunscreen agents in patients with
`rosacea. They conducted a cheek—versus—cheek com—
`parison of 4 test lotions and used a 4—point scale to
`score stinging at 1 minute.3 Padimate 0 without
`dimethicone or cyclomethicone was significantly
`more irritating than a p—aminobenzoic acid—free
`sunscreen that contained both silicones (P = .0267).
`However,
`the
`addition
`of dimethicone
`and.
`cyclomethicone to the padimate O sunscreen re—
`duced its irritancy, making it equivalent
`to the
`p—aminobenzoic acid—free lotion (P = .78). Nichols
`et al concluded that the presence or absence of
`protective ingredients was more important
`than
`the presence or absence ofp—aminobenzoic acid.5
`
`COSMETICS
`
`_
`
`Cosmetic intolerance and facial skin “sensitivity”
`are common features of the erythematotelangiectatic
`Amneal 1059
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`This material may be protected by Copyright law (Title 17 U.S. Code)
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`J AM ACAD DERMATOL
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`Table 1. Guidelines for the use of sunscreen and
`
`cosmetics in rosacea patients with sensitive skin and
`barrier dysfunction
`
`Cleansers should be soap free.
`Choose sunscreens that protect against ultraviolet A and
`ultraviolet B light. “Physical blockers” (titanium dioxide
`and zinc oxide) are best tolerated.
`Cosmetics and sunscreens should contain protective
`silicones (dimethicone or cyclomethicone).
`Choose a light foundation that is easy to spread and can
`be set with powder. (Foundations that contain
`ultraviolet A—ultraviolet B sunscreen are encouraged.)
`Green—tinted makeup or sunscreen can provide extra
`coverage of red areas.
`Avoid astringents, toners, menthols, camphor, and
`products that contain sodium lauryl sulfate.
`Avoid waterproof cosmetics and heavy foundations that
`are harder to apply and remove without irritating
`solvents.
`
`and papulopustular subtypes of rosacea. In a series
`of 52 rosacea patients, 75% experienced stinging
`after application of 5% lactic acid, compared with
`19% of 32 control patients.4 All 7 erythematotel—
`angiectatic patients experienced stinging, as did 17 of
`25 papulopustular patients. It is common for many
`cosmetic formulations to dry and irritate rosacea—
`prone skin, possibly because of barrier dysfunction
`or vascular hyperreactivity.4“6 Instructing patients to
`avoid irritating ingredients is not effective because it
`is often the interaction among chemicals or their
`concentration, not their presence,
`that promotes
`cutaneous irritation.7
`
`A few formulations are problematic for the sensi—
`tive skin of erythematotelangiectatic and papu—
`lopustular patients, and a warning to avoid them is
`appropriate. Astringents, toners, menthol, and cam—
`phor—containing products are examples. Patients
`should similarly avoid products that contain sodium
`lauryl sulfate, an irritating anionic surfactant.7 Table 1
`provides guidelines for cosmetic use in patients with
`rosacea. Cleansers should be soap free, and. products
`should be applied with the fingers to reduce barrier
`(ilisruption.7’8 Removal of waterproof cosmetics and
`heavy foundations is difficult without irritating sol—
`vents
`and should. be
`avoided.
`Instead,
`light
`foundations that can be set with powder are
`recommended.7 Ideally, a light liquid foundation
`makeup should contain a silicone for barrier pro—
`tection in addition to a broad—spectrum sunscreen.
`Green~tinted makeup may also be used for extra
`coverage of red areas. Patients should first apply the
`green tint to red areas, then apply a layer of founda—
`tion makeup.
`I
`
`In addition to the avoidance of harsh products,
`patients with cosmetic intolerance and barrier sensi—
`
`tivity should. be encouraged. to apply a protective,
`gentle emollient to the face once or twice daily,
`preferably before the application of other products.
`Substantial decreases in papule counts and. erythema
`have been routinely identified as placebo effects in
`randomized, controlled trials of numerous topical
`rosacea therapies versus emollient cream vehicles.
`Repair and protection of the stratum corneum rep—
`resents an important adjunct for rosacea patients
`with barrier deficiency.
`
`TOPICAL MEDICATIONS
`
`Three topical medications have been approved by
`the Food and Drug Administration (FDA) for rosacea.
`All are indicated for the management of papules,
`pustules, and erythema. They include 5 varieties of
`0.75% metronidaZOle (Metrocream, Metrogel, and
`Metrolotion, Galderma Laboratories, Fort Worth,
`Tex)
`and 1% metronidazole
`(Noritate
`cream,
`Dermik Laboratories, Berwyn, Pa), several brands
`of 10% sodium sulfacetamide with 5% sulfur
`
`lotions, Dermik
`(Sulfacet—R tinted. and tint—free
`Laboratories, Berwyn, Pa, Plexion cleanser and
`topical
`suspension, Medicis
`Pharmaceutical
`Corporation,
`Scottsdale, AZ; Rosanil
`cleanser,
`Galderma Laboratories, Fort Worth, Tex; Rosula
`lotion, Doak Dermatologics, Fairfield, NJ; Clenia
`foaming cleanser and emollient cream, Upsher—
`Smith, Minneapolis, Minn; Rosac cream, Stiefel
`Laboratories, Inc, Coral Gables, Fla; Avar Green color
`corrective gel, CollaGenex Pharmaceuticals: Inc,
`Newtown, Pa) and 15% azelaic acid gel (Finacea,
`Berlex Laboratories, MontVille, NJ). Several other
`topical medications are used off label for rosacea.
`
`METRONIDAZOLE
`
`Pye and Burton first reported success with oral
`metronidazole for rosacea in 1976.9 Nielsen was the
`
`first to demonstrate the effectiveness of a topical
`metronidazole formulation for rosacea during the
`early 1980s.”12 Over the years, debate has sur—
`rounded its most effective strength and dosing
`regimen. The 0.75% formulation was marketed. first
`in the United States, and optimal dosing was de—
`termined to be twice daily, based on a half—life of 6
`hours. for the gel formulation.15 Dahl et al
`later
`established the effectiveness of once—daily dosing,
`independent of strength. In a multicenter, 12—week
`randomized trial that included. 72 patients, Dahl et al
`found no significant difference between once—daily
`application of the 1% and. 0.75% formulations with
`respect
`to reduction of erythema, papules, and.
`pustules; global assessment of severity; dryness;
`
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`JAM ACAD DERMATOL
`VOLUME 51, NUMBER 4
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`1
`
`treatment failure; and safety.” Topical metronida~
`zole is rated B in pregnancy category.
`Many double—blind, placebo—controlled trials of
`topical metronidazole have demonstrated beneficial
`effects
`in
`the
`treatment
`of
`rosacealo’lz’m”20
`
`Breneman et al compared the efficacy of once-daily
`metronidazole 1% cream with that of the vehicle
`
`alone in 139 patients. Significant reductions in in—
`flammatory lesions were reached at 4 weeks.19
`Erythema reduction has been demonstrated in mul—
`tiple studies,10’13’1/"’19'21 but there is conflict regard—
`ing the onset of effect. Erythema reduction ’with
`metronidazole 1% daily therapy has reached. signif—
`icance as early as week 220 and as late as week 10,19
`depending on the series. Vehicle cream alone (ap—
`plied twice daily) achieved a 28% reduction in the
`erythema score in one trial.20
`The effectiveness of topical metronidazole has
`been favorably compared to that of low—dose tetra—
`cycline therapy, although tetracyclines achieve a
`fasterclinical response.22 In a double—blind study of5 1
`patients with rosacea, 1% metronidazole (plus pla—
`cebo tablet) was compared with oxytetracycline (250
`mg twice daily, plus placebo cream).10 There was no
`difference in objective or subjective improvement
`between the 2 groups after 2 months of therapy. After
`discontinuation of oral therapy, topical metronida—
`zole appears to maintain remission better than the
`vehicle alone, as demonstrated in a multicenter,
`randomized, double—blind trial in which 25% of 59
`subjects who underwent maintenance with metroni—
`dazole gel experienced relapse, versus 42% of 45
`subjects who applied a vehicle gel (P < .05).8’25
`Other data have supported. this finding.12
`
`SODIUM SULFACETAMIDE AND SULFUR
`Sodium sulfacetamide 10% and sulfur 5% in
`
`combination have undergone a resurgence recently
`in the treatment of both acne and rosacea. The
`
`combination is in pregnancy category C. For more
`than 50 years, it has provided. a safe, well—tolerated,
`and effective option for
`the treatment of acne
`vulgaris, rosacea, perioral dermatitis, and seborrheic
`dermatitis?!“25 The use of sodium sulfacetamide and
`
`sulfur combinations is contraindicated in patients
`with sulfonamide hypersensitivity and in patients
`with kidney disease.
`Sauder et al conducted an 8—week double—blind,
`placebo—controlled trial
`in 94 rosacea patients to
`evaluate the effectiveness of sodium sulfacetamide
`and sulfur lotion for rosacea.26 At week 8, inflamma—
`tory lesions were decreased by 78% in patients who
`applied. the sodium sulfacetamide and sulfur lotion,
`compared with a 36% decrease in patients given
`placebo. Erythema decreased 85% from baseline in
`
`Pelle, Crawford, amaljames 501
`
`the sodium sulfacetamide—sulfur group versus 51%
`in control patients. Lebwohl et al evaluated the
`combination lotion versus metronidazole 0.75% gel
`in an investigator—blinded trial of 63 patients with
`rosacea over 8 weeks.27 On the basis of physician
`global assessment at weeks 6 and 8,
`the sodium
`sulfacetamide—sulfur group achieved significantly
`lower papule and pustule scores, erythema scores,
`and overall severity ratings compared with the
`metronidazole gel group. Adverse reactions (pruri—
`tus, contact dermatitis, irritation, and xerosis) related
`to sodium sulfacetamide—sulfur occurred in 19% of
`patients and were mild.27
`Twice—daily Cleansing with sodium sulfacetamide
`10% and sulfur 5% was evaluated alone and in
`
`combination with metronidazole therapy (0.75%) in
`an 8—week investigator—blinded controlled study of
`moderate rosacea in 50 patients.22 The cleanser was
`an effective monotherapy, achieving significant re—
`ductions of papule counts and erythema. However,
`the combination of sodium sulfacetamide—sulfur
`
`cleanser followed by metronidazole cream was su—
`perior to the cleanser alone in the reduction of
`papule counts and overall rosacea severity.
`Benefits of the newer “wash—on—wash—off” so—
`dium sulfacetamide—sulfur
`formulations
`include
`
`easy incorporation as a combination modality, less
`lingering odor, lower irritation potential, improved
`absorption through hydrated skin,28 and fewer in—
`teractions with other topical regimens or cosmetics.
`Masking fragrances are added to many of the topical
`“leave on” sulfur formulations, but their characteris~
`tic odor does reappear gradually after application.
`
`AZELAIC ACID
`
`The FDA approved azelaic acid 15% gel (Finacea)
`in December 2002 for the treatment of mild to
`
`moderate rosacea. Azelaic acid. is a naturally occur—
`ring saturated dicarboxylic acid.29 Like metronida—
`zole, azelaic acid. is thought to inhibit or reduce. the
`production
`of
`reactive
`oxygen
`species
`by
`neutrophils.50 It is in pregnancy category B.
`Two phase III vehicle—controlled,
`randomized.
`trials have demonstrated the effectiveness and safety
`of 15% azelaic acid gel in 664 patients with pap—
`ulopustular rosacea.51 Improvement of erythema
`occurred. in 44% and 46% of patients in the azelaic
`acid groups versus 29% and 28% of vehicle—treated
`patients. The mean reductions of inflammatory
`lesions in the azelaic acid—treated patients were
`58% and 51%, versus 40% and 39% in control
`patients. At baseline, two-thirds of patients in both
`treatment groups reported skin dryness. Thirty—eight
`percent of patients who underwent treatment with
`azelaic acid experienced burning, stinging, or itching
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`502 P9116, Crawford, omdjames
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`I AM ACAD DERMATOL
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`related to the therapy, and. these symptoms were
`transient in 70% of those affected. Approximately
`12% of patients experienced scaling, skin dryness, or
`rash with the use of azelaic acid gel.51
`In a smaller double—blind, randomized, split—face
`trial of 40 patients with papulopustular rosacea, the
`effectiveness of 20% azelaic acid cream was com~
`
`pared with that of topical metronidazole 0.75%
`cream over a 15—week period.52 Papule and pustule
`counts were decreased by 78.5% in the azelaic acid.
`group, compared with 69.4% in the metronidazole
`group. Most patients (92%) said. they would continue
`to use azelaic acid, although transient stinging did
`occur in some patients. 2’52
`
`BENZOYL PEROXIDE
`
`Benzoyl peroxide can trigger stinging and ery—
`thema in some rosacea patients with barrier dysfunc—
`tion and “sensitive” skin. In contrast, rapid. resolution
`of erythematous papules and. pustules can be
`achieved in nonsensitive patients (personal observa—
`tion, M.T.P., W.DJ.), and a recent trial of benzoyl
`peroxide—Clindamycin combination therapy has
`shown promise in patients with moderate rosacea
`(data in press, personal communication withJames P.
`Leyden, MD). With few exceptions, patients with
`phymatous and glandular rosacea tolerate the drug
`quite well, and their inflammatory disease can often
`be controlled. with benzoyl peroxide or benzoyl
`peroxid e—clindamycin combination therapy. Benzoyl
`peroxide is in pregnancy category C.
`
`ERYTHROMYCIN AND CLINDAMYCIN
`
`Mills and Kligman originally described the use of
`topical erythromycin base for
`the treatment of
`rosacea in 1976, when they were prompted by their
`successful results in acne vulgaris.55 After 4 weeks of
`twice—daily topical erythromycin (in a vehicle of
`equal parts water and ethanol), reduction of ery—
`thema and suppression of papules and pustules were
`noted in 157 of 15 patients?5 Side effects included
`transient stinging and dryness.
`Clindamycin lotion is less popular for rosacea but
`has been compared favorably to oral tetracycline
`therapy in an investigator—blinded 12—week trial of 43
`patients. Topical Clindamycin (twice daily) produced
`clearance that was similar to oral tetracycline (1,000
`mg/d for 3 weeks, tapered to 500 mg/d for 9 weeks),
`and topical Clindamycin was more effective than
`tetracycline for the eradication of pustules.54 Both
`erythromycin and Clindamycin are in pregnancy
`category B.
`
`TACROLIMUS
`
`Topical tacrolimus has been reported to be an
`effective treatment for steroid—induced. rosacea—like
`eruptions.35’56 Tacrolimus 0.1% ointment (Protopic,
`Fujisawa Healthcare, Inc, Deerfield, IL) is a macrolide
`nonsteroidal immunomodulatory agent approved in
`the United States for the treatment of atopic derma—
`titis. Goldman treated 3 patients with steroid—induced.
`rosacea—like eruption using a 0.075% tacrolimus
`preparation twice daily for 7 to 10 days.55 None of
`his patients was given oral tetracyclines concomi—
`tantly, but they were instructed to avoid topical
`steroids and rosacea triggers. Goldman noted. that
`pruritus, erythema, and tenderness were resolved in
`each patient at the end of the 10—day treatment
`period.55 Our observation in many such patients
`affirms the utility of tacrolimus; we find that using
`tacrolimus twice daily combined. with 100 mg of
`minocycline twice daily for 1 to 2 months clears most
`patients.
`
`TRETINOIN
`
`Dermal inflammation, elastin and collagen de—
`generation, and alteration of the cutaneous vascula—
`
`the prominent histologic features of
`ture are
`rosacea?”9 Topical tretinoin promotes connective
`tissue remodeling in the papillary and reticular
`dermis and minimizes dermal
`inflammation with
`chronic therapy/’0"42 Therefore,
`it is not surprising
`that topical retinoids have demonstrated benefit for
`rosacea, although their clinical response is delayed,
`often not evident until 2 or more months into
`therapy“45 Ertl and colleagues noted. the delayed
`response in 20 rosacea patients who underwent
`treatment with an oral or topical retinoid, or both,
`for 8 months, although their study was not well
`controlled. They noted improvement after 8 weeks of
`topical tretinoin monotherapy and after 4 weeks of
`isotretinoin, alone or in combination with tretinoin.46
`Their study included patients with “erythema with
`significant papules and/or pustules” and. those with
`“disease activity incompletely controlled by prior
`therapies,” including patients with “only modest
`numbers of inflammatory lesions.”46
`In 1999 Vienne et al treated 23 women with “mild”
`
`rosacea (10 patients with diffuse erythema, 10
`with erythema and telangiectasia, and 5 with only
`telangiectasia) with 0.05% retinaldehyde cream/15
`Retinaldehyde was used instead. of retinoic acid
`because of its better tolerability/g’z18 Facial
`ery—
`thema was measured with a spectrophotometer
`(Chromameter CR 200, Minolta, Tokyo, japan). All
`patients completed the 6~month study with minimal
`signs of irritation. At 4 weeks a 10% decrease in
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`I AM ACAD DERMATOL
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`
`1I
`
`erythema Was detected by means of spectrophotom—
`etry.45 At 5 months a clinical response was noted in
`75% of the 20 patients with erythema (P < .05).
`Patients with only telangiectasia showed a lesser
`response.
`Despite their intuitive appeal for rosacea based on
`histologic findings and positive observations in a few
`small
`series,43’46’49 topical
`retinoids have been
`avoided because of their potential for irritation and
`concerns regarding possible promotion of angiogen—
`esis.50’51 It has been suggested that
`the use of
`tretinoin in rosacea may promote the development
`of telangiectasia by stimulating cutaneous neovas—
`CUlai’iZathH.44’50 In 1995 Kligman described “note—
`worthy” angiogenesis in tretinoin—treated, non—sun—
`eXposed skin of the elderly.“ However, his findings
`were not accompanied by a visible increase in
`cutaneous vascularity or the development of telan—
`giectasia. Vienne et al did not observe an increase in
`telangiectasia in their patients after 6 months of
`retinaldyhyde therapy, although longer—term fol—
`low—up was not provided!"5 Likewise, years of topical
`tretinoin therapy in thousands of patients with facial
`photoaging have not uncovered a tendency for
`tretinoin to promote telangiectases. In fact the in—
`hibitory effects of retinoids on vascular endothelial
`growth factor production by cultured. human skin
`keratinocytes have been described;
`those effects
`occur via their anti—APl
`transcription factor activ—
`ity.41’52 Indeed, their antiangiogenic properties con—
`tribute partly to their success as antineoplastic
`agents.55 Tretinoin is in pregnancy class C.
`
`ORAL MEDICATIONS
`
`Tetracyclines
`Tetracycline has been a mainstay of rosacea
`therapeutics for more than 40 years, although it has
`not been approved by the FDA for treatment of this
`condition. Sneddon performed a double—blind, pla—
`cebo—controlled trial of tetracycline for rosacea in
`1966 to evaluate its effects on the “erythematous and
`papular type” and the “pustular form” of rosacea.54
`He treated 78 patients with either tetracycline, 250
`mg twice daily, or placebo for 4 weeks, followed. by
`a 4—week period during which all patients underwent
`treatment with tetracycline. At 1 month, 78% of the
`tetracycline—treated patients had improvement,
`whereas 45% of the placebo—treated patients did.
`During the second month, improvement occurred in
`an additional 74% of patients who had not previously
`received tetracycline. Eleven percent of the patients
`given tetracycline for 8 weeks had. no improve
`ment.“ In those patients, “redness rather than pus—
`tulation was the main element of [their] rosacea.”
`
`P6119, Crawford, andfames 505
`
`tetracycline is
`A 5— to 4~week course of oral
`generally required. to achieve substantial improve—
`ment in signs and symptoms.57’S4 Both Marks and
`Sneddon noted that clearance of rosacea could be
`achieved at subantimicrobial dosages,37'54 and. Marks
`added. that “it is probable that the action of tetracy—
`cline in rosacea is not antibacterial.” Sneddon
`
`achieved good maintenance with 250 mg daily or
`with 250 mg every other day, but hevnoted frequent
`relapses upon stopping the drug.54 Knight and
`Vickers studied 68 rosacea patients and reported
`a 24% relapse rate within 1 month of tetracycline
`withdrawal (250 mg twice daily). Within 6 months
`after stopping therapy, 60% of their patients had
`recurrences.55 The authors did not consider residual
`
`erythema active disease. Thirty-one percent of their
`patients maintained remission off therapy after 4
`years of follow—up.55
`The second—generation tetracyclines, which in—
`clude minocycline, doxycycline hyclate, and doxy—
`cycline monohydrate, are similarly effective for
`rosacea, although controlled trials are lacking. In
`comparison with their parent drug,
`the second—
`generation tetracyclines have a longer elimination
`half—life and improved bioavailability, and can be
`taken with food, minimizing gastrointestinal side
`effects.56 Second—generation tetracyclines may alSo
`achieve beneficial effects for rosacea patients at
`subantimicrobial dosing. Clinical
`trials are under
`way to evaluate subantimicrobial—dose doxycycline
`hyclate (Periostat, CollaGeneX Pharmaceuticals, Inc.,
`Newtown, PA)
`for
`the treatment of
`rosacea.S7
`Periostat
`is indicated for the treatment of adult
`
`periodontal disease, with its mechanism attributed
`to its anticollagenase and antimatriX metalloproa
`teinase properties.”59 Preliminary results have
`shown improvement in some features of rosacea
`with the use of subantimicrobial—dose doxycycline
`hyclate (20 mg twice daily), but long—term studies in
`which its efficacy is compared. with that of antimi—
`crobial—dose tetracyclines are required to determine
`whether subantimicrobial—dose doxycycline hyclate
`achieves improvement and remission as reliably, as
`rapidly, and for as long a period. If it were proved
`effective, its major benefit would be less microbial
`resistance with long—term therapy. Oral tetracyclines
`should be avoided in pregnant woman and those
`contemplating pregnancy.
`
`Macrolides
`
`Oral erythromycin therapy is employed for
`rosacea especially when there is intolerance, allergy,
`or resistance to tetracyclines or when there are
`contraindications to tetracycline use such as preg~
`
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`

`504 P9116, Crawford, (malformes
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`1 AM ACAD DERMATOL
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`
`pared with basal values. Benefits of the second—
`
`generation macrolides are improved bioavailability
`and lack of gastrointestinal side effects in comparison
`with'erythromycin. Controlled clinical trials are nec—
`essary to determine the role of second——gene1ation
`mac101ides in both initial and maintenance the1apy
`fo1 1osacea. A cost compa11S01’l of the various antimi—
`crobial the1apies fo1 rosacea can be found1n Table II.
`
`have been camouflaged by xerosis and de1matitis
`
`Table 11. Cost comparison of various oral antimi—
`crobial therapies used in the treatment of rosacea
`
`
` Medication Dose (mg) Cost"
`
`
`
`Tetracycline HCI capsules
`
`.
`
`Metronidazole tablets
`Flagyl tablets
`Erythromycin base (enteric—coated)
`capsules
`Erythromycin base tablets
`Minocycline HCI capsules
`
`Minocin capsules
`
`Dynacin capsules
`
`_
`
`250
`500
`250
`250
`250
`
`500
`50
`100
`
`50
`100
`50
`100
`
`7.99
`7.99
`8.86
`58.99
`8.99
`
`8.15
`13.99
`21.99
`
`62.99
`101.99
`72.08
`127.72
`
`Docycycline hyclate tablets
`Doxycycline monohydrate capsules
`
`12.50
`100
`33.99
`50
`45.99
`100
`‘ 27.49
`20
`Periostat tablets
`107.49
`250
`Clarithromycin (Biaxin) tablets
`
`Azithromycin (Z—pak) tablets 214.95 250
`
`
`Source: Drugstorecom online pharmacy (www.drugstore.com);
`accessed July 15, 2003.
`*Prices, in US dollars, are based on a 30—tablet or —capsu|e supply.
`
`lactation, and age younger than 12 years.
`nancy,
`Erythromycin is in category B for pregnancy.
`The
`second—generation macrolides, Clarithro—
`mycin‘and azithromycin, have demonstrated effec—
`tiveness for rosacea in recent studies.60”62 In an
`8—week trial, 40 patients underwent treatment with
`either Clarithromycin (250 mg twice daily for 4
`weeks, followed by 250 mg once daily for 4 weeks)
`or doxycycline (100 mg twice daily for 4 weeks,
`followed by 100 mg Once daily for 4 weeks).60
`Clarithromycin achieved significantly faster
`re—
`ductions of e1‘ythema (P < .005) and papules (P <
`.0005) than doxycycline did at weeks 4 and 6. No
`significant differences in erythema reduction, telan—
`giectasia, or papule and pustule counts were found
`between the 2 drugs at week 8. The authors con—
`cluded that 6 weeks of Clarithromycin therapy was as
`efficacious askS weeks of doxycycline therapy.
`Clarithromycin also had better tolerability scores
`during the entire duration of therapy.60 After 5 years
`of follow—up, patients who underwent treatment
`with Clarithromycin required the drug 10. 2 weeks
`per year compared with 14.6 weeks1for patients who
`underwent doxycycline t1.eatment6
`rosacea
`Az1th1omyc1n was evaluated in 18
`patients, 14 of which completed. the 12—week trial.62
`Patients were given oral azithromycin for 1 2 weeks in
`decreasing doses. At the end of the trial, there was an
`89% decrease in inflammatory lesion scores com—
`
`Metronidazole
`
`Oral metronidazole is an effective alternative for
`the treatment of rosacea, utilized mo1e often as initial
`and as long—term 1osacea the1apy by Eu1opean
`practitione1s. 96565 In 1976 Pye and Bu1ton reported
`thei1 eXpe1ience with 29 patients in whom 1osacea
`was treated with 200 mg of oral metronidazole twice
`daily. Improvement in papule and pustule counts
`was significant after 6 weeks of therapy. All of the
`patients also applied. hydrocortisone cream to their
`faces twice daily. Despite that addition, they noted
`minimal e1ythema reduction during the 6—week trial.9
`In a double—blind, randomized trial, Saihan com—
`pared the efficacy of oral metronidazole, 200 mg
`twice daily, with oxytetracycline, 250 mg twice daily,
`in 58 patients with papulopustular rosacea. At 6 and
`12 weeks, there was no difference between the 2
`
`therapies, but both drugs showed sustained im—
`provement at 12 weeks. Abstinence from alcohol
`during metronidazole therapy is necessa1y to avoid
`alcohol—induced headaches via disulfiram reac~
`tions.65 Although it is 1elatively safe, metronid6azole
`1arely h21657 been associated with neu1opathy6§ and
`seiZur.6es7The chug is well tolerated during p1eg—
`nancy (catego1y B) and p1ovides an alternative
`when tetracyclines are prohibited or ir1effective.65’68
`A meta—analysis to assess the risk of birth defects
`while taking metronidazole during the first trimester
`showed no relationship between metronidazole ex
`posure and congenital 111alformations.68
`
`Isotretinoin
`
`Multiple small studies from the 1980s established
`the effectiveness of isot1etinoin for rosacea. 6975 The
`effects of isot1etinoin can be delayed in compa1ison
`with standa1d the1apies,4674' although a reduction of
`papule counts may be evident as early as 2 weeks.70
`I1vine, Kumar, and Marks treated erythematotelan—
`giectatic and papulopustular rosacea with either
`oxytetracycline (n = 6; 250 mg twice daily) or iso—
`tretinoin (n = 5; 50 mg daily) for a 2—month period.
`All patients had improvement, but the oxytetracy—
`Cline group had bette1 global assessment sco1es
`(1eduction of e1ythema, papules, and pustules) at 8
`weeks.75 Erythema 1eduction by isot1etinoin may
`
`

`

`J AM ACAD DERMATOL
`VOLUME 51, NUMBER 4
`
`1
`
`associated with its use. Minimal erythema has
`been persistent in responsive patients until late into
`therapy.70’75
`Although interpretation is limited by their small
`sample size, Irvine, Kumar, and Marks observed,
`using a laser—Doppler device (Perimed), that cutane—
`ous blood flow on the cheek, when measured at 25°C
`and 54°C, was not reduced in patients who under—
`went oxytetracycline treatment. In contrast, patients
`in the isotretinoin group showed significantly re—
`duced facial cutaneous blood flow by means of laser—
`Doppler at both temperatures at 10 weeks.75
`Erdogan et al more recently studied the short—term
`effects of low—dose isotretinoin in 22 patients with
`treatment—resistant rosacea. Patients were given 10
`mg daily for 4 months.
`Isotretinoin significantly
`reduced inflammatory papules, pustules, erythema,
`and telangiectasia at 9 weeks.“ Results were further
`improved at 16 weeks. Ocular lesions regressed at 3
`weeks. On the basis of these promising observations,
`it canbe said that larger, more powerful studies are
`needed. to establish the short— and long—term benefits
`of isotretinoin for rosacea.
`Isotretinoin has also been demonstrated. to de—
`
`crease nasal volume in rhinophyma.70'7S The most
`significant regression has been noted in younger
`patients with less advanced disease.75 Biopsy spe—
`cimens from phymatous skin prior to isotretinoin
`therapy showed numerous large sebaceous glands.
`During isotretinoin therapy, the glands diminished in
`size and. number. Other studies have confirmed the
`usefulness of isotretinoin for phymatous change.76’77
`
`MISCELLANEOUS ORAL THERAPIES
`
`In 1971 Spirov, Berova, and Vassilev described the
`benefits of oral contraceptive monotherapy in 50
`women with rosacea.78 Before therapy they docu—
`mented “historical and clinical abnormalities of hor—
`
`monal origin” in 21 of their 30 patients. Complete
`resolution of papular lesions and improvement of
`erythema occurred in 18 patients (60%), with maX—
`imal effects requiring 4 months of therapy.78 Mauss
`treated 5 women with a combination of oral contra—
`
`ceptive plus 10 mg of cyproterone acetate daily
`between days 5 and 19 of the menstrual cycle.
`Papules and pustules cleared in each patient by 3
`months; however, telangiectasia persisted.79
`The antiandrogenic effects of spironolactone have
`also been evaluated for rosacea. Thirteen men with
`rosacea underwent treatment with a low dose of
`spironolactone (50 mg daily), and their serum hor—
`mone levels were evaluated prior