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`DOI: 10.1111/j.1468-3083.2009.03167.x
`
`JEADV
`
`
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`
`
`REVIEW ARTICLE
`Current topical and systemic approaches to treatment of rosacea
`
`HC Korting,* C Schöllmann
`
`Department of Dermatology and Allergology, Ludwig-Maximilians-Universität, Munich, Germany
` HC Korting.
` h.c.korting@lrz.uni-muenchen.de
`*Correspondence:
`E-mail:
`
`Abstract
`Rosacea is a common, often overlooked, chronic facial dermatosis characterized by intermittent periods of exacerbation
`and remission. Clinical subtypes and grading of the disease have been defined in the literature. On the basis of a genetic
`predisposition, there are several intrinsic and extrinsic factors possibly correlating with the phenotypic expression of the
`disease. Although rosacea cannot be cured, there are several recommended treatment strategies appropriate to control
`the corresponding symptoms/signs. In addition to adequate skin care, these include topical and systemic medications
`particularly suitable for the papulopustular subtype of rosacea with moderate to severe intensity. The most commonly
`used and most established therapeutic regimens are topical metronidazole and topical azelaic acid as well as oral
`doxycycline. Conventionally, 100–200 mg per day have been used. Today also a controlled release formulation is
`available, delivering 40 mg per day using non-antibiotic, anti-inflammatory activities of the drug. Anti-inflammatory dose
`doxycycline in particular allows for a safe and effective short- and long-term therapy of rosacea. Topical metronidazole
`and topical azelaic acid also appear to be safe and effective for short-term use. There are indications that a combined
`therapy of anti-inflammatory dose doxycycline and topical metronidazole could possibly have synergy effects. Further
`interesting therapy options for the short- and long-term therapy of rosacea could be low-dose minocycline and
`isotretinoin; however, too little data are available with regard to the effectiveness, safety, optimal dosage and appropriate
`length of treatment for these medications to draw final conclusions.
`Received: 21 December 2007; Accepted 9 December 2008
`
`Keywords
`azelaic acid, doxycycline, metronidazole, rosacea
`
`Conflicts of interest
`.
`None declared
`
`Introduction
`Rosacea is a common, but often overlooked, chronic cutaneous
`disease of uncertain aetiology with many different clinical
`manifestations.
` The dermatological condition primarily affects
`1
`the centre of the face, especially the cheeks, nose, chin and central
`forehead. Furthermore, ocular manifestations may be present,
`possibly occurring more frequently than previously presumed.
`2
`The earliest and not rarely predominant complaints linked to
`rosacea are intermittent, central facial flushing and erythema.
`Many patients complain of a stinging pain associated with
`episodes of flushing while itching is nearly always absent.
`Flushing episodes can occur unpredictably or can be linked to
`environmental, chemical, food or emotional triggers (i.e.
`exposure to sun, cold weather, hot beverages, sudden emotion
`like laughter or embarrassment and alcohol consumption).
` The
`1
`progression of rosacea is variable; however, typical stages are
`represented by papules and pustules and, finally, rhinophyma.
`
`Epidemiology
`Conventional wisdom has it that rosacea is more common in
`women,
` while the clinical manifestations of the disease are
`3
`more severe in men.
` By contrast, a recent analysis based on a
`4
`cross sectional study of rosacea (1995 2002) on 50 235 outpatients
`shows that overall, both sexes were equally affected by the disease.
`5
`Epidemiological data at large suggest that there is a genetic
`predisposition for this disease, with several intrinsic and extrinsic
`factors potentially correlating with the phenotypic expression of
`rosacea.
`6
`Rosacea most frequently occurs in the light skinned Caucasian
`population, and in persons between 30 and 50 years.
` Estimates
`1,3,7
`of the prevalence of rosacea range from less than 1% to 10%.
` A
`4,5,8
`recent investigation suggests that the prevalence of rosacea has
`been substantially underestimated. Among 850 females aged up to
`70 years recruited from the general population in London and Los
`Angeles, 174 (20.5%) were identified as having rosacea, with
`
`JEADV
` 2009,
`23
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`, 876–882
`
`Journal compilation © 2009
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`© 2009 The Authors
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`1 of 7
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`Approaches to treatment of rosacea
`
`877
`
` In
`rosacea prevalence decreasing with the degree of skin colour.
`9
`contrast, data collected by the Rochester Epidemiology Project
`indicate a rosacea prevalence of 2.1% among adults, suggesting
`that the actual occurrence of the disease is rarer than previously
`reported.
`
`Pathophysiology
`There is a lack of understanding with regard to the pathogenesis
`of rosacea. The important issue of whether or not the papules are
`based in the follicle is still unclear at this time.
` It is also unknown
`10
`if accumulated sun damage might be involved in the pathogenesis,
`and, furthermore, whether neurological and hormonal mechanisms
`are involved in flushing reaction and phyma formation and, if so,
`which ones (for review, see Baldwin
`). What is known is that the
`10
`pathophysiology of rosacea likely is inflammatory, and that most
`interventions appear to modulate the inflammatory process.
`11,12
`Moreover, there is a growing consensus that bacterial infection
`most likely is not involved in rosacea pathogenesis.
` Because of
`10
`the poor understanding of the pathogenesis of rosacea, treatment
`has generally targeted the symptoms/signs rather than the
`potential underlying causes of the disease. Despite the incomplete
`understanding of the pathogenesis of rosacea, therapeutic options
`
`continue to expand (for review, see Pelle et al.
`).
`13
`
`Classification and staging
`A standard classification system for rosacea was published in
`April 2002.
` Developed by the National Rosacea Society Expert
`14
`Committee on the Classification and Staging of Rosacea and
`reviewed by rosacea experts worldwide, it describes primary and
`secondary features of the disease. Primary features were identified
`as flushing (transient erythema), nontransient erythema, papules
`and pustules and telangiectasia. Secondary features were identified
`as burning or stinging, presence of plaques, dry appearance,
`presence of oedema, peripheral location (extrafacial signs and
`symptoms) and phymatous changes.
` Finally, the committee
`14
`recognized four patterns of signs and symptoms, designated as
`subtypes.
`Subtype 1 (erythematotelangiectatic rosacea) is characterized
`by flushing and persistent central facial erythema with tel
`angiectases common but not essential. Subtype 2 (papulopustular
`rosacea) includes persistent central facial erythema with transient
`papules, pustules, or both in a central facial distribution. Burning
`and stinging may also occur. Subtype 3 (phymatous rosacea) may
`include thickening of the skin, irregular surface nodularity, and
`enlargement (e.g. as rhinophyma). Patulous, expressive follicles
`may appear in the phymatous area, and telangiectases may be
`present as well. Subtype 4 (ocular rosacea) may be characterized
`by a watery or bloodshot appearance, foreign body sensation,
`burning or stinging, dryness, itching, light sensitivity, blurred
`vision and telangiectasia of the conjunctiva and lid margin; lid and
`periocular erythema, blepharitis, conjunctivitis and irregularity of
`the eyelid may also be present. Using the National Rosacea Society
`
`Expert Committee’s standard classification system, among 177
`women with rosacea recruited from the general population in
`London and Los Angeles recently (as cited above
`), 161 (92.6%)
`14
`were considered to have subtype 1 while only 13 (7.4%) had
`the papulopustular subtype 2. Fourteen women (8%) had ocular
`involvement and seven (4%) rhinophyma.
`9
`To enhance the utility of the classification system, the Committee
`devised a standard method for assessing different grades of
`severity.
` As indicated in the proposals of the Committee, primary
`15
`signs may be graded as absent, mild, moderate or severe (0 3), and
`most secondary features may be graded simply as absent or
`present.
` According to the researchers, such a standard grading
`15
`system in combination with a standard classification system is
`often useful and essential in analysing results from different
`sources and performing research. In turn, standard parameters
`and terminology may provide a common reference for the
`diagnosis, treatment and estimation of results in clinical practice.
`The recent study among 177 women with rosacea already
`addressed above suggests that mild disease is more common in
`females with subtype 1, affecting almost 75% of those individuals,
`while the skin disease severity was graded as moderate in 19% of
`the women with subtype 1 and severe in 9%.
`9
`Classification of the polymorphic disease rosacea into four
`subtypes is also controversial among some researchers. For example,
`Albert M. Kligman believes that reducing the disease to four main
`types is a vast oversimplification and does little to clarify the
`complexities of this entity.
` For Kligman and other researchers,
`4
`rosacea fundamentally is a vascular disorder beginning with
`episodes of flushing and histopathologically showing classic signs
`of damage to the dermal matrix; namely, elastosis, collagenolysis
`and increased glycaminoglycans.
`4
`
`Therapy of rosacea
`
`Therapy based on rosacea subtypes
`Although rosacea is a disease that causes high psychological strain
`in those affected, it has no adverse effect on vital functions. For
`this reason, preference should be made for medications with an
`especially favourable risk profile.
`The four subtypes differ greatly with regard to their response to
`various therapy strategies. The erythematotelangiectatic subtype
`is the most difficult to treat. Most patients respond poorly to
`topical or oral medications. There are some data indicating that
`isotretinoin transiently may improve erythema resulting from
`inflammation, while medications that antagonize flushing may be
`helpful for other patients.
` Vascular laser and light therapy have
`10
`been increasingly utilized for control of the generalized erythema,
`flushing, and telangiectasia characteristic for this subtype of
`rosacea.
` Mild forms of ocular rosacea respond readily to topical
`16,17
`medications and eyelid hygiene; more severe forms substantially
`respond to oral antibiotics, with tetracyclines being used most
`often.
` There is a limit to the use of topical and/or oral medications
`10
`
`JEADV
` 2009,
`, 876–882
`23
`
`© 2009 The Authors
`Journal compilation © 2009 European Academy of Dermatology and Venereology
`
`2 of 7
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`878
`
`Korting and Schöllmann
`
`in the treatment of phymatous rosacea. Often surgery or laser
`ablation is necessary to eradicate very pronounced lesions.
`10
`Isotretinoin, in particular, has been shown to have the potential to
`
`et al., as cited in
`delay the progression of rhinophyma (Irvine
`Baldwin
`) and to be an option for patients with treatment resistant
`10
`rosacea.
` The papulopustular subtype of rosacea is the easiest type
`18
`to treat. A lot of patients respond well to topical medications such
`as metronidazole, azelaic acid, benzoyl peroxide, clindamycin,
`and erythromycin.
` Sometimes, however, topical medications
`10
`reach the limitations of their effectiveness. At this point at the
`latest, a systemic therapy is necessary. Since 2006, topical
`medications are no longer being applied as a first line therapy
`in the USA in all cases. With the advent of a once daily, non
`antibiotic dosing of doxycycline as a therapy option, the systemic
`approach is being used more often as a first choice medication.
`6
`In addition, recent studies suggest that a combined therapy
`(e.g. once daily, anti inflammatory doxycycline combined
`with topical metronidazole) might possibly further increase
`effectiveness
`.
`19,20
`The therapy options discussed in detail in the following primarily
`address the problems of patients with the moderate to severe
`papulopustular subtype.
`
`Topical medications
`Three topical medications have been approved by the US Food
`and Drug Administration (FDA) for rosacea, and all three,
`including 0.75% and 1% metronidazole, 10% sodium with 5%
`sulphur, and 15% azelaic acid, are indicated for the management
`of papules, pustules and erythema.
` Moreover, other medications
`13
`are used off label for this disease.
`
`Metronidazole
`In the 1980s, it was shown for the first time that topical
`metronidazole can be used successfully in the treatment of
` Today, besides azelaic acid (see below), metronidazole
`rosacea.
`21
`is considered the first choice for the topical therapy of rosacea.
`Twice daily metronidazole (0.75%) was well tolerated and effective
`in the treatment of 582 patients with mild to moderately severe
`papulopustular rosacea of various aetiologies and locations. Its
`mean erythema severity score decreased significantly and was
`reduced by nearly 50% by week 12.
` For a long time, a twice daily
`22
`application of 0.75% gel formulation was considered to be the
`optimal dosage until the effectiveness of a once daily dosage of
`0.75% and 1% metronidazole formulation could be shown in a
`12 week, randomized study.
` In 2006, it was moreover shown
`23
`that the type of formulation in fact might play a subordinate role
`with regard to effectiveness: metronidazole cream, gel and lotion
`have been shown to have similar efficacy, regardless of whether
`a concentration of 0.75% or 1% is chosen or a once daily or
`twice daily regimen.
`24
`The efficacy of topical metronidazole vs. a placebo has been
`demonstrated in various trials; however, only nine of these were of
`
`acceptable quality. In these studies, metronidazole was found to
`be an effective medication with few adverse effects, whereby most
`of the adverse effects were mild, including pruritus, skin irritation
`et al.
`and dry skin (see Van Zuuren
`). A new, stable aqueous
`25
`metronidazole gel (1%) might possibly even be a better tolerated
`alternative with a low potential for causing sensitization reactions
`and no evidence for causing phototoxic or photo allergic reactions.
`26
`In patient self assessment, there was no statistical difference
`between topical azelaic acid and topical metronidazole, whereas a
`significantly higher physician rating of global approvement was
`achieved with azelaic acid.
` However, the difference between
`27,28
`the two medications with regard to the reduction of inflammatory
`lesions was too marginal to be of clinical relevance.
` A new
`28
`study shows that the efficacy of the once daily application of
`metronidazole (1% gel) and twice daily azelaic acid 15% gel was
`similar.
` Both medications were well tolerated, but the number of
`29
`adverse effects was lower after application of metronidazole
`whereby the adverse effects in both groups have been reported be
`mild to moderate.
` Furthermore, topical metronidazole might
`28
`be as effective as oral tetracycline,
` benzoyl peroxide 5%/eryth
`21,30
`romycin 3% gel,
` and topical permethrin (5% cream),
` but more
`31
`32
`evidence is needed.
`
`Sodium sulphacetamide and sulphur
`For more than 50 years, sodium sulphacetamide 10% with sulphur
`5% has provided a safe, well tolerated and effective option for
`the treatment of rosacea,
` but the quality of studies concerning
`13
`this matter is generally poor. By means of an 8 week therapy,
`a significant reduction in inflammatory lesions (78% vs. 36%,
`P
`respectively;
`< 0001) and facial erythema (83% vs. 31%,
`P
`respectively;
`< 0001) was achieved compared to a vehicle.
`33
`Adverse effects (pruritus, contact dermatitis, irritation, and xerosis)
`occurred in 19% of users, but they were reported to be mild
`et al.
`et al.
`(Lebwohl
`, as cited in Pelle
`). Anecdotal evidence and
`13
`preliminary studies suggest at least some additional benefit
`when sodium sulphacetamide 10%/sulphur 5% is applied in
`combination with topical metronidazole.
` Moreover, newer
`34
`‘wash on wash off’ sodium sulphacetamide formulations have
`further additional benefits such as less lingering odour, lower
`irritation potential and fewer interactions with other topical
`regimens or cosmetics (Arndt and Bowers, as cited in Pelle
`et al.
`). Generally, there is insufficient evidence concerning the
`13
`effectiveness of sulphacetamide with sulphur in the treatment of
`rosacea.
`
`Azelaic acid
`Azelaic acid, mostly applied as 15% gel or 20% cream, is a
`naturally occurring saturated dicarboxylic acid
` approved for the
`35
`treatment of mild to moderate rosacea in various countries. Its
`effectiveness and safety has been demonstrated in two phase III,
`vehicle controlled, randomized trials in 664 patients with
`papulopustular rosacea. In these studies, improvement of erythema
`
`JEADV
` 2009,
`23
`
`, 876–882
`
`© 2009 The Authors
`Journal compilation © 2009 European Academy of Dermatology and Venereology
`
`3 of 7
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`

`Approaches to treatment of rosacea
`
`879
`
`was found in 44% and 46% ofrosacea patients treated with azelaic
`acid vs. 29% and 28% of patients treated with a vehicle.36 Analysis
`of the reduction of inflammatory papules and pustules led to
`comparable results.37
`
`Benzoyl peroxide, erythromycin and clindamycin
`Benzoyl peroxide, erythromycin and clindamycin are sometimes
`used ofl' label in the treatment of rosacea although there are not
`rmny studies available covering these three medications.
`
`Tacrolimus
`
`Topieal tacrolimus (0.1 or 0.075% 96 ointment) is a macrolide
`non steroidal immunomodulatory preparation approved in the
`USA that acts by inhibiting T cell activation and cytokine release.”
`It is approved so far for the treatment ofatopic dermatitis only but
`has also been reported to be an effective treatment for steroid
`induced rosacea,”"” yet there are not many studies available in
`this regard. It has been claimed that tacrolimus twice daily
`combined with 100 mg of minocycline (twice daily) clears most
`patients with steroid induced rosacea within 1 2 months.”
`
`Tretinoin
`
`In a few small series, topieal retinoids like tretinoin have
`demonstrated benefit for rosacea. although the clinical response is
`delayed and often not evident until 2 or more months after
`initiation of therapy." ‘3 The use of topieal retinoids in rosaoea
`has often been avoided because of the possible angiogenesis
`supporting effects of this substance group, yet so far a visible
`increase in cutaneous vascularity or the development of
`telangiectasia has not been observed.‘m In contrast, a lessening
`of erythema and a partial
`to complete disappearance of
`telangiectasia has been reported in patients treated with 0.025%
`tretinoin cream" However, on the whole, the trial situation for
`
`this medieation is relatively poor.
`
`Oral medications
`Oral antibiotics have been used 0E label for the treatment of
`
`rosacea for more than 50 years, and tetracyclines have been the
`drug class most often used. Antibiotics were used to treat rosacea
`based on the presumption (and from today’s view a presumption
`that is most likely wrong) that bacterial pathogens are, in part,
`responsible for the development of the disease.‘0
`
`Tetracyclines
`Tetracyclines are broad spectrum antibiotics that have been used
`in rosacea treatment for deeades although never approved by the
`FDA for this indieation." They were first widely prescribed by
`dermatologists in the 19503 when it was discovered that they were
`effective in the treatment of acne. Tetracycline has also been
`reported to be effective in the treatment of papulopustular
`rosacea, in which context a 3 or 4 week treatment regimen
`was required to achieve substantial improvement.“ Tetracycline
`
`
`
`Flgm 1 Chemical structure of doxycycline.
`
`(250 1000 mg per day), doxycycline (100 200 mg per day, and
`lately also 20 40 mg per day) and minocycline (100 200 mg per
`day) are the most commonly used compounds. '° Tetracyclines are
`contraindieated in pregnant women. Until recently, the use oforal
`tetracyclines for rosacea was based primarily on clinieal experience
`anda limited number ofplacebo controlled studies?“ Only the
`most recent studies were conducted on the basis of a suficiently
`large number of patients reflecting their generally high quality.6
`but nevertheless further randomized, controlled studies are
`needed.
`
`Today researchers for the most part agree that it is mainly the
`non antibiotic properties of the various tetracyclines that are
`responsible hr the eflectiveness ofthese substances in skin diseases
`such as rosacea. In fact, it is the non antibiotic actions oftetracyclines
`such as the inhibition ofangiogenesis, the inhibition ofneutrophil
`chemotaxis, the inhibition of pro inflammatory cytokines and
`the inhibition of matrix metalloproteinases that significantly
`contribute to the clinieal effectiveness for various indieations
`in
`
`addition to rosacea also being used for bullous dermatoses,
`neutrophil diseases, periodontitis and autoimmune disorders such
`as rheumatoid arthritis and sderoderma, pyoderma gangrenosum.
`sarcoidosis, aortic aneurysms, and cancer." In particular, the
`ability of tetracyclines to reduce the inflammatory response is
`believed to be the rationale for its effectiveness in treating rosacea
`(Greewald et aL, as cited in Baldwin”).
`Besides the classic drug, tetracycline itself, today second genera
`tion tetracyclines, including minocycline and especially doxycyeline
`(Fig. l), are being successfully used in the treatment of rosacea. In
`comparison with their parent drug, these tetracyclines can ofier
`advantages to the dermatologist over tetracycline. For example,
`they have an improved bioavailability, a longer elimination half life,
`and they an be taken with (bod which minimizes gastrointestinal
`side effects.“ A big advantage of these substances, moreover, is
`represented by the fact that they are helpful for rosacea patients
`already at a sub antimicrobial (also at a time anti inflammatory)
`dose.‘ Thus, an effective and tolerable long term therapy is
`possible without having to accept the disadvantages ofa long term
`antibiosis, i.e. undesired side effects such as eandidal vulvovaginitis
`or gastrointestinal distress. and of worldwide importance
`the
`propagation of bacterial resistance.‘9 As bacterial resistance is a
`
`IEADV 2009, 23. 876—882
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`880
`
`Korting and Schollmann
`
`global problem, the use of non antibiotic alternatives such as
`low dose doxycycline should be preferred in the treatment of
`rosacea where there is no established evidence of a microbial
`
`pathogenesis.’o
`Anti inflammatory dose doxycycline is the only tetracycline
`approved in the USA for long term use for up to 12 months.” The
`used dosage of 20 mg doxycycline hyclate twice daily or 40 mg
`once daily has been shown to effectively treat papulopustular
`rosacea with an especially favourable risk benefit ratio. The first
`oral medication approved by the FDA for the treatment ofrosacea
`in the USA is marketed as Oracea“. Oracea' is a 40 mg capsule of
`doxycycline monohydrate containing 30 mg immediate release
`and 10 mg delayed release doxycycline beads. In contrast to other
`oral therapies, anti inflamImtory dose doxycycline is taken once
`daily, which may increase treatment compliance.” Furthermore,
`it has been shown that a 40 mg controlled release formulation of
`doxycycline conferred peak anti inflamrmtory efficacy in the
`treatment of rosacea.‘o At sub antimicrobial doses, long term use
`of anti inflammatory dose doxycycline might not exert selective
`pressure on micro organisms, and thus not lead to the development
`of antibiotic resistant organisms'w'“. Recently, two phase III,
`parallel group, multicentre, randomized, double blind, placebo
`controlled studies have demonstrated the eflieacy and safety of a
`16 week treatment with anti inflammatory doxycycline (40 mg)
`administered once daily in patients with rosacea.‘ Both studies
`included patients with a marked number ofinflammatory lesions
`(10 40 papules, < 2 nodules), moderate to severe erythema and
`the presence of telangiectasia. Patients received 40 mg ofcontrolled
`release doxycycline (n = 269) or placebo (n = 268) for 16 weeks.
`The primary endpoint was the mean change from baseline in
`inflammatory lesion count. At week 16, the mean change from
`baseline in lesion count in the doxycycline groups was
`11.8 in
`one study and 9.5 in the other study compared with 5.9 and 4.3,
`respectively, in the placebo groups (P < 0.001 for both comparisons,
`Figs 2 and 3). The active medication was well tolerated with
`nasopharyngitis (4.8%), diarrhoea (4.4%) and headaches (4.4%)
`constituting the most common adverse efiects being found only
`marginally more frequently than in the control group, if at all.‘
`Thus, today anti inflammatory doxycycline (40 mg) administered
`once daily must be considered to be
`besides topical therapies
`with metronidazole or azelaic acid a promising therapy strategy
`for rosacea of papulopustular subtype.
`Current research on comparably small patient numbers suggests
`that a combined therapy of anti inflammatory dose doxycycline
`and topical metronidazole (0.75% topieal lotion or 1% topical gel)
`leads to an especially effective alleviation of inflammatory lesions.
`The therapeutic effect might be greater and set in faster than with
`metronidazole alone" (Fowler, 2007, poster presented at: American
`Academy of Dermatology 65th Annual Meeting; February 2 6,
`2007; Washington, DC). Yet reliable data are not available as to
`whether the efiectiveness ofthe combination is better than that of
`
`anti inflammatory dose doxycycline alone.
`
`
`=o.oos 'P<0.001' P<o.oo1I P<0.001
`
`
`
`count
`
`inflammatorylesion
`
` MeanchangeIntotal
`
`Baseline
`
`Week 3
`
`+ Doxycycline
`
`Week 6
`+
`
`Week 12
`Placebo
`
`Week 16
`
`Figue 2 Mean change from baseline in total inflammatory lesion
`count (papules + pustules + nodulee)ihrough week 16 in study 301
`(from Del Roeeo et al.‘ with permission).
`
`P< 0.001
`
`P< 0.001
`
`P< 0.001
`
`—2
`
`\= 0.005
`
`
`count I
`
`inflammatoryIeslon
`
` MeanchangeIntotal
`
`_| 0
`
`Baseline
`
`Week 3
`
`Week 6 Week 12 Week 16
`
`+ Doxycycllne + Placebo
`
`Figue 3 Mean change from baseline in total inflammatory lesion
`count (papules + pustules + nodulee)through week 16in study 302
`(From Del Rosso at al.5with permission).
`
`Macrolides
`
`Although oral erythromycin at a dose of 250 1000 mg per day is
`considered an effective drug for the treatment of papulopustular
`rosacea,
`it is not often used because of the gastrointestinal
`side effects it frequently causes.” As a general rule, the use of
`erythromycin is reserved for those patients that are intolerant,
`allergic or refractory to tetracyclines or in eases where tetracyclines
`are contraindieated, such as in pregnancy.'3
`As second generation macrolides. clarithromycin and azi
`thromycin take effect faster and are better tolerated with regard to
`gastrointestinal side eflects than orally administered tetracyclines,
`metronidazole and ketoconazole.52 In several smaller studies, both
`
`have been found to be eEective and tolerable drugs in the short
`term therapy of rosacea.52 5‘ After a 12 week treatment with
`azithromycin in decreasing doses, there was a 75% decrease in
`total scores and an 89% decrease in inflammatory lesion scores
`
`IEADV 2009. 23. 876—882
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`0 2039 The Authors
`Journd compilation 0 2009 Euopean Mademy of DermatologyandVenereology
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`50f7
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`Approaches to treatment of rosacea
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`881
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`54
`
` According to a trial with a 3 year
`compared with basal values.
`follow up, rosacea patients that were treated with clarithromycin
`required a significantly shorter treatment period (10.2 weeks) than
`patients who received an antibiotic effective dose (200 mg per
`day) of doxycycline.
` Controlled clinical trials are necessary to
`52
`further elucidate the role of second generation macrolides in both
`short term and, in particular, long term therapy for rosacea.
`
`Isotretinoin
`Isotretinoin is one of the few drugs which elicit a response with
` but the quality of studies concerning
`several subtypes of rosacea,
`10
`this matter is generally very poor. Only small trials of low quality
`are available, whether randomized nor blinded, whose results
`have to be interpreted very carefully. In one of these small studies,
`isotretinoin was effective for both erythematotelangiectatic and
`papulopustular rosacea, including a reduced facial cutaneous
`blood flow in the isotretinoin group but not in the comparison
`et al.
`, as cited in
`group treated with oxytetracycline (Irvine
`Baldwin
`). Another study on 22 patients shows the effectiveness
`10
`of a 4 month low dose isotretinoin therapy (10 mg per day) in
`patients with therapy resistant rosacea. The treatment led to a
`reduction of inflammatory lesions, erythema and telangiectasia.
`19
`Overall the effect of isotretinoin therapy was delayed in
`comparison to therapy with oral antibiotics.
`18,55
`
`Metronidazole
`Oral metronidazole was reported to be successful in the treatment
`of rosacea for the first time in 1976. A 6 week therapy with twice
`daily 200 mg oral metronidazole significantly reduced papules
`and pustules in 29 patients.
` A randomized study investigated the
`56
`effectiveness of oral metronidazole (200 mg twice daily) or
`oxytetracycline (250 mg twice daily). Both drugs produced an
`improvement after 6 and especially after 12 weeks of therapy, but
`there was no significant difference between them.
` In rare cases,
`57
`treatment with oral metronidazole might be associated with
`epileptiform seizures, encephalopathy, and sensory neuropathy.
`58
`It requires abstinence from alcohol.
`57
`Besides the drugs described, the literature mentions drugs that
`improve flushing reactions in particular cases. These include, for
`example, propanolol, clonidine, nadolol, naloxone, ondansetron,
`acetyl salicylic acid, and some selective serotonin reuptake inhib
`itors.10 However, there is insufficient evidence for the effectiveness
`of these substances.
`
`Conclusions
`An array of topical and systemic therapy options exist for the
`therapy of rosacea, especially for the papulopustular subtype.
`Many of these options have already existed for decades. However,
`sufficient evidence with regard to effectiveness and tolerability
`only exists for a few of the active pharmacological ingredients and
`treatments used. According to data currently available, topical
`metronidazole and azelaic acid can be regarded as essentially safe.
`
`Both allow for a safe and effective short term treatment of
`papulopustular rosacea, whereby azelaic acid has a slight
`advantage with regard to efficacy, and metronidazole with regard
`to tolerability. Among systemic drugs, low dose non antibiotic
`doxycycline, especially with the once daily application approach,
`is the most interesting and, based on recent studies, the best
`supported therapy option. Fortunately, it can also be used as a
`therapy on a long term basis. Currently, no criteria exist for
`determining under which conditions preference should be made
`for topical or systemic therapy strategies. Since 2006, that is, since
`once daily, non antibiotic dose doxycycline is available in the
`USA, there seems to be a trend to move towards using the systemic
`therapy with doxycycline as first line monotherapy and not to
`reserve it for those patients only who did not experience success
`with topical therapy. Further studies must show whether
`combination therapies (e.g. with oral non antibiotic dose
`doxycycline and topical metronidazole) lead to a further increase
`in efficacy in rosacea
` what should indeed meet the expectations
`of at least a remarkable subgroup of bothered patients.
`
`References
`1 Blount BW, Pelletier AP. Rosacea: a common yet commonly overlooked
`condition. Am Fam Physician 2002; 66: 435–440, 442.
`2 Eiseman AS. The ocular manifestations of atopic dermatitis and rosacea.
`Curr Allergy Asthma Rep 2006; 6: 292–298.
`3 Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol
`1989; 69: 419–423.
`4 Kligman AM. A personal critique on the state of knowledge of rosacea.
`Dermatology 2004, 2008: 191–198.
`5 Kyriakis KP, Palamaras I, Terzoudi S, Emmanuelides S, Michailides C,
`Pagana G. Epidemiologic aspects of rosacea. J Am Acad Dermatol 2005; 53:
`918–919.
`6 Del Rosso JQ, Webster GF, Kackson 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.
`7 Fel