DOD: 10.1111/i.i 468-3083.2009.03167.x J£ADV
`
`REVIEW ARTICLE
`Current topical and systemic approaches to treatment of rosacea
`
`HC Korting,* C Sch611mann
`
`Department of Dermatology and Allergology, Ludwig-Maximilians-UniversitAt, Munich, Germany
`
`*Correspondence: HC Korting. E-mail: h.c.korting@lrz.uni-muenchen.de
`
`Abstr~ot
`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
`
`Ke~azcerds
`azelaic acid, doxycycline, metronidazole, rosacea
`
`¢e~flicts of interest
`None declared.
`
`ENdemio~ogy
`~ntreductien
`Rosacea is a common, but often overlooked, chronic cutaneous Conventional wisdom has it that rosacea is more common in
`disease of uncertain aetiology with many different clinical women,3 while the clinical manifestations of the disease are
`manifestations.1 The dermatological condition primarily affects more severe in men? By contrast, a recent analysis based on a
`the centre of the face, especially the cheeks, nose, chin and central
`cross-sectional study ofrosacea (1995-2002) on 50 235 outpatients
`forehead. Furthermore, ocular manifestations may be present,
`shows that overall, both sexes were equally affected by the disease?
`possibly occurring more frequently than previously presumed.2 Epidemiological data at large suggest that there is a genetic
`The earliest and not rarely predominant complaints linked to
`predisposition for this disease, with several intrinsic and extrinsic
`rosacea are intermittent, central facial flushing and erythema,
`factors potentially correlating with the phenotypic expression of
`Many patients complain of a stinging pain associated with
`rosacea.6
`episodes of flushing while itching is nearly always absent.
`Rosacea most frequently occurs in the light-skinned Caucasian
`Flushing episodes can occur unpredictably or can be linked to
`population, and in persons between 30 and 50 years.1’3’r Estimates
`environmental, chemical, food or emotional triggers (i.e.
`of the prevalence ofrosacea range from less than 1% to 10%.4’5’8 A
`exposure to sun, cold weather, hot beverages, sudden emotion
`recent investigation suggests that the prevalence of rosacea has
`like laughter or embarrassment and alcohol consumption).1 The
`been substantially underestimated. Among 850 females aged up to
`progression of rosacea is variable; however, typical stages are
`70 years recruited from the general population in London and Los
`Angeles, 174 (20.5%) were identified as having rosacea, with
`represented by papules and pustules and, finally, rhinophyma.
`
`]EADV 2009, 23,876-882
`
`© 2009 The Authors
`Journal compilation © 2009 European Academy of Dermatology and Venereology
`
`1 of 7
`
`Almirall EXHIBIT 2019
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`Approaches to treatment of rosacea
`
`877
`
`rosacea prevalence decreasing with the degree of skin colour.9 In Expert Committee’s standard classification system, among 177
`contrast, data collected by the Rochester Epidemiology Project women with rosacea recruited from the general population in
`indicate a rosacea prevalence of 2.1% among adults, suggesting London and Los Angeles recently (as cited above14), 161 (92.6%)
`that the actual occurrence of the disease is rarer than previously were considered to have subtype 1 while only 13 (7.4%) had
`reported,
`the papulopustular subtype 2. Fourteen women (8%) had ocular
`involvement and seven (4%) rhinophyma.9
`Pathophysio~o~};~:
`To enhance the utility of the classification system, the Committee
`devised a standard method for assessing different grades of
`There is a lack of understanding with regard to the pathogenesis
`ofrosacea. The important issue of whether or not the papules are
`severity)5 As indicated in the proposals of the Committee, primary
`signs may be graded as absent, mild, moderate or severe (0- 3), and
`based in the follicle is still unclear at this time)° It is also unknown
`if accumulated sun damage might be involved in the pathogenesis, most secondary features may be graded simply as absent or
`and, furthermore, whether neurological and hormonal mechanisms
`present)5 According to the researchers, such a standard grading
`system in combination with a standard classification system is
`are involved in flushing reaction and phyma formation and, if so,
`often useful and essential in analysing results from different
`which ones (for review, see Baldwin1°). What is known is that the
`sources and performing research. In turn, standard parameters
`pathophysiology of rosacea likely is inflammatory, and that most
`and terminology may provide a common reference for the
`interventions appear to modulate the inflammatory process)u2
`diagnosis, treatment and estimation of results in clinical practice.
`Moreover, there is a growing consensus that bacterial infection
`most likely is not involved in rosacea pathogenesis)° Because of The recent study among 177 women with rosacea already
`the poor understanding of the pathogenesis ofrosacea, treatment
`addressed above suggests that mild disease is more common in
`females with subtype 1, affecting almost 75% of those individuals,
`has generally targeted the symptoms/signs rather than the
`potential underlying causes of the disease. Despite the incomplete while the skin disease severity was graded as moderate in 19% of
`understanding of the pathogenesis ofrosacea, therapeutic options
`the women with subtype 1 and severe in 9%.9
`continue to expand (for review, see Pelle et al)3).
`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.4 For Kligman and other researchers,
`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
`
`O~assification and stagir~g
`A standard classification system for rosacea was published in
`April 2002.14 Developed by the National Rosacea Society Expert
`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, Therapy of rosacea
`presence of oedema, peripheral location (extrafacial signs and
`Therapy based on rosacea subtypes
`symptoms) and phymatous changes)4 Finally, the committee
`recognized four patterns of signs and symptoms, designated as Although rosacea is a disease that causes high psychological strain
`subtypes,
`in those affected, it has no adverse effect on vital functions. For
`Subtype 1 (erythematotelangiectatic rosacea) is characterized
`this reason, preference should be made for medications with an
`by flushing and persistent central facial erythema with tel-
`especially favourable risk profile.
`angiectases common but not essential. Subtype 2 (papulopustular
`The four subtypes differ greatly with regard to their response to
`rosacea) includes persistent central facial erythema with transient
`various therapy strategies. The erythematotelangiectatic subtype
`papules, pustules, or both in a central facial distribution. Burning
`is the most difficult to treat. Most patients respond poorly to
`and stinging may also occur. Subtype 3 (phymatous rosacea) may
`topical or oral medications. There are some data indicating that
`include thickening of the skin, irregular surface nodularity, and
`isotretinoin transiently may improve erythema resulting from
`enlargement (e.g. as rhinophyma). Patulous, expressive follicles
`inflammation, while medications that antagonize flushing may be
`may appear in the phymatous area, and telangiectases may be
`helpful for other patients)° Vascular laser and light therapy have
`present as well. Subtype 4 (ocular rosacea) may be characterized
`been increasingly utilized for control of the generalized erythema,
`by a watery or bloodshot appearance, foreign-body sensation,
`flushing, and telangiectasia characteristic for this subtype of
`burning or stinging, dryness, itching, light sensitivity, blurred
`rosacea)6a7 Mild forms of ocular rosacea respond readily to topical
`vision and telangiectasia of the conjunctiva and lid margin; lid and medications and eyelid hygiene; more severe forms substantially
`respond to oral antibiotics, with tetracyclines being used most
`periocular erythema, blepharitis, conjunctivitis and irregularity of
`the eyelid may also be present. Using the National Rosacea Society
`often)° There is a limit to the use of topical and/or oral medications
`
`JEADV 2009, 23,876-882
`
`© 2009 The Authors
`Journal compilation © 2009 European Academy of Dermatology and Venereology
`
`2 of 7
`
`

`

`878
`
`Korting and Sch611mann
`
`acceptable quality. In these studies, metronidazole was found to
`in the treatment of phymatous rosacea. Often surgery or laser
`be an effective medication with few adverse effects, whereby most
`ablation is necessary to eradicate very pronounced lesions.1°
`of the adverse effects were mild, including pruritus, skin irritation
`Isotretinoin, in particular, has been shown to have the potential to
`and dry skin (see Van Zuuren et al.25). A new, stable aqueous
`delay the progression of rhinophyma (Irvine et al., as cited in
`Baldwin1°) and to be an option for patients with treatment-resistant metronidazole gel ( 1% ) might possibly even be a better tolerated
`alternative with a low potential for causing sensitization reactions
`rosacea?8 The papulopustular subtype ofrosacea is the easiest type
`to treat. A lot of patients respond well to topical medications such
`and no evidence for causing phototoxic or photo-allergic reactions.26
`as metronidazole, azelaic acid, benzoyl peroxide, clindamycin,
`In patient self-assessment, there was no statistical difference
`and erythromycin.1° Sometimes, however, topical medications
`between topical azelaic acid and topical metronidazole, whereas a
`reach the limitations of their effectiveness. At this point at the
`significantly higher physician rating of global approvement was
`latest, a systemic therapy is necessary. Since 2006, topical
`achieved with azelaic acid.27’28 However, the difference between
`medications are no longer being applied as a first-line therapy
`the two medications with regard to the reduction of inflammatory
`in the USA in all cases. With the advent of a once-daily, non-
`lesions was too marginal to be of clinical relevance.28 A new
`study shows that the efficacy of the once-daily application of
`antibiotic dosing of doxycycline as a therapy option, the systemic
`approach is being used more often as a first choice medication.6 metronidazole (1% gel) and twice-daily azelaic acid 15% gel was
`In addition, recent studies suggest that a combined therapy
`similar.29 Both medications were well tolerated, but the number of
`(e.g. once-daily, anti-inflammatory doxycycline combined
`adverse effects was lower after application of metronidazole
`with topical metronidazole) might possibly further increase whereby the adverse effects in both groups have been reported be
`effectiveness19’2°.
`mild to moderate.28 Furthermore, topical metronidazole might
`The therapy options discussed in detail in the following primarily
`be as effective as oral tetracycline,21’3° benzoyl peroxide 5 %/eryth-
`address the problems of patients with the moderate to severe
`romycin 3% gel,31 and topical permethrin (5% cream),32 but more
`papulopustular subtype,
`evidence is needed.
`
`Topicai 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?3 Moreover, other medications
`are used off-label for this disease,
`
`Sodium suiphacetamid÷ and suiphur
`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,13 but the quality of studies concerning
`this matter is generally poor. By means of an 8-week therapy,
`a significant reduction in inflammatory lesions (78% vs. 36%,
`respectively; P < 0001) and facial erythema (83% vs. 31%,
`respectively; P < 0001) was achieved compared to a vehicle.33
`~e~ro~°~idazol÷
`Adverse effects (pruritus, contact dermatitis, irritation, and xerosis)
`occurred in 19% of users, but they were reported to be mild
`In the 1980s, it was shown for the first time that topical
`metronidazole can be used successfully in the treatment of
`(Lebwohl et al., as cited in Pelle et al.13). Anecdotal evidence and
`preliminary studies suggest at least some additional benefit
`rosacea.21 Today, besides azelaic acid (see below), metronidazole
`is considered the first choice for the topical therapy of rosacea, when sodium sulphacetamide 10%/sulphur 5% is applied in
`Twice-daily metronidazole (0.75%) was well-tolerated and effective
`combination with topical metronidazole.34 Moreover, newer
`in the treatment of 582 patients with mild to moderately severe
`’wash-on-wash-off’ sodium sulphacetamide formulations have
`papulopustular rosacea of various aetinlogies and locations. Its
`further additional benefits such as less lingering odour, lower
`irritation potential and fewer interactions with other topical
`mean erythema severity score decreased significantly and was
`reducedbynearly50%byweek 12.22 For a long time, atwice-daily
`regimens or cosmetics (Arndt and Bowers, as cited in Pelle
`application of 0.75% gel formulation was considered to be the
`et al.13). Generally, there is insufficient evidence concerning the
`optimal dosage until the effectiveness of a once-daily dosage of
`effectiveness of sulphacetamide with sulphur in the treatment of
`0.75% and 1% metronidazole formulation could be shown in a
`rosacea.
`12-week, randomized study.23 In 2006, it was moreover shown
`that the type of formulation in fact might play a subordinate role A~eiaic aoid
`with regard to effectiveness: metronidazole cream, gel and lotion Azelaic acid, mostly applied as 15% gel or 20% cream, is a
`
`have been shown to have similar efficacy, regardless of whether
`
`naturally occurring saturated dicarboxylic acid35 approved for the
`
`a concentration of 0.75% or 1% is chosen or a once-daily or
`
`treatment of mild to moderate rosacea in various countries. Its
`
`twice-daily regimen.24
`
`effectiveness and safety has been demonstrated in two phase-Ill,
`
`The efficacy of topical metronidazole vs. a placebo has been
`
`vehicle-controlled, randomized trials in 664 patients with
`
`demonstrated in various trials; however, only nine of these were of
`
`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
`
`

`

`Approaches to treatment of rosacea
`
`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
`
`OH
`
`O
`
`OH
`
`O
`
`8enzoyl peroxid% er}*thromycin and clindarnycin
`Benzoyl peroxide, erythromycin and clindamycin are sometimes
`used off-label in the treatment of rosacea although there are not
`many studies available covering these three medications.
`
`H’" CHa
`
`(CHa)2
`
`Figure 1 Chemical structure of doxycycline.
`
`879
`
`. H~O
`
`Tretinoin
`In a few small series, topical 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.4~ 43 The use of topical retinoids in rosacea
`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.41’43 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.4~ However, on the whole, the trial situation for
`this medication is relatively poor.
`
`Tacrolimus
`Topical tacrulimus (0.1 or 0.075% % ointment) is a macrolide
`non-steroidal immunomodulatory preparation approved in the
`(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
`USA that acts by inhibiting T-cell activation and cytokine release.38
`It is approved so far for the treatment ofatopic dermatitis only but
`day) are the most commonly used compounds.1° Tetracyclines are
`contraindicated in pregnant women. Until recently, the use of oral
`has also been reported to be an effective treatment for steroid-
`induced rosacea,39’4° yet there are not many studies available in
`tetracyclines for rosacea was based primarily on clinical experience
`and alimitednumberofplacebo-controlledstudies.13,45,46 Only the
`this regard. It has been claimed that tacrolimus twice daily
`combined with 100 mg of minocycline (twice daily) clears most most recent studies were conducted on the basis of a sufficiently
`patients with steroid-induced rosacea within 1-2 months)3
`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 for the effectiveness 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 clinical effectiveness for various indications - in
`addition to rosacea also being used for bullous dermatoses,
`neutrophil diseases, periodontitis and autoimmune disorders such
`as rheumatoid arthritis and scleroderma, pyoderma gangrenosum,
`sarcoidosis, aortic aneurysms, and cancer.4r 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 Baldwin1°).
`Besides the classic drug, tetracycline itself, today second genera-
`tion tetracyclines, including minocycline and especially doxycycline
`(Fig. 1), are being successfully used in the treatment of rosacea. In
`comparison with their parent drug, these tetracyclines can offer
`advantages to the dermatologist over tetracycline. For example,
`they have an improved bioavailability, a longer elimination half life,
`and they can be taken with food which minimizes gastrointestinal
`side effects.48 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.6 Thus, an effective and tolerable long-term therapy is
`possible without having to accept the disadvantages of a long-term
`antibiosis, i.e. undesired side effects such as candidal vulvovaginitis
`or gastrointestinal distress, and - of worldwide importance - the
`propagation of bacterial resistance.49 As bacterial resistance is a
`
`Oram medications
`Oral antibiotics have been used off-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)°
`
`Tetraoyolines
`Tetracyclines are broad-spectrum antibiotics that have been used
`in rosacea treatment for decades although never approved by the
`FDA for this indication)3 They were first widely prescribed by
`dermatologists in the 1950s 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.44 Tetracycline
`
`JEADV 2009, 23,876-882
`
`© 2009 The Authors
`Journal compilation © 2009 European Academy of Dermatology and Venereology
`
`4 of 7
`
`

`

`880
`
`Korting and Sch611mann
`
`global problem, the use of non-antibiotic alternatives such as
`low-dose doxycycline should be preferred in the treatment of
`"E
`rosacea where there is no established evidence of a microbial ~ og
`pathogenesis.10
`~_’8 _g
`Anti-inflammatory dose doxycycline is the only tetracycline
`& g
`
`~ "~
`
`0
`
`"~’QP-- 0.005 ’ P< 0.001 ’ P< 0.001 ’ P< 0.001
`-2 N~
`X"~.~
`
`-6
`
`-4 \ __
`
`-14
`
`’
`’
`’
`Baseline Week 3
`Week 6 Week 12 Week 16
`--*--Doxycycline ~ Placebo
`
`’
`
`Figure 2 Mean change from baseline in total inflammatory lesion
`count (papules + pustules + nodules) through week 16 in study 301
`(from Del Rosso et al.° with permission).
`
`0
`
`-2
`
`-4
`
`-6
`
`-8
`
`~
`=_=
`
`XP= 0.005 ’ P < 0.001 ’ P < 0.001 ’ P < 0.001
`
`~
`
`~-~......~
`
`-10 i i i i
`Baseline Week 3 Week 6 Week 12 Week 16
`
`Doxycycline
`
`-~- Placebo
`
`Figure 3 Mean change from baseline in total inflammatory lesion
`count (papules + pustules + nodules)through week 16 in study 302
`(From Del Rosso et al.° with permission).
`
`approved in the USA for long-term use for up to 12 months.1° The
`-8
`used dosage of 20 mg doxycycline hyclate twice daily or 40 mg
`~ gE -10
`once daily has been shown to effectively treat papulopustular ~= ~
`-"’--~-_~..
`.~ -12
`rosacea with an especially favourable risk-benefit ratio. The first
`oral medication approved by the FDA for the treatment of rosacea
`in the USA is marketed as OraceaZ 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-inflammatory dose doxycycline is taken once
`daily, which may increase treatment compliance.49 Furthermore,
`it has been shown that a 40-mg controlled release formulation of
`doxycycline conferred peak anti-inflammatory efficacy in the
`treatment of rosacea.5° 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 organisms1°’49’51. Recently, two phase III, ~o
`.c_ ._o
`parallel-group, multicentre, randomized, double-blind, placebo-
`& g
`controlled studies have demonstrated the efficacy and safety of a
`~
`g {
`16-week treatment with anti-inflammatory doxycycline (40 mg)
`administered once daily in Patients with rosacea.6 Both studies
`included patients with a marked number of inflammatory lesions
`(10-40 papules, < 2 nodules), moderate to severe erythema and
`the presence of telangiectasia. Patients received 40 mg of controlled-
`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 effects being found only ~*taogolid÷s
`marginally more frequently than in the control group, if at all.6 Although oral erythromycin at a dose of 250-1000 mg per day is
`considered an effective drug for the treatment of papulopustular
`Thus, today anti-inflammatory doxycycline (40 mg) administered
`once daily must be considered to be - besides topical therapies
`rosacea, it is not often used because of the gastrointestinal
`with metronidazole or azelaic acid- a promising therapy strategy
`side effects it frequently causes?° As a general rule, the use of
`erythromycin is reserved for those patients that are intolerant,
`for rosacea ofpapulopustular subtype,
`Current research on comparably small patient numbers suggests
`allergic or refractory to tetracyclines or in cases where tetracyclines
`are contraindicated, such as in pregnancy?3
`that a combined therapy of anti-inflammatory dose doxycycline
`and topical metronidazole (0.75% topical lotion or 1% topical gel)
`As second-generation macrolides, clarithromycin and azi-
`leads to an especially effective alleviation of inflammatory lesions,
`thromycin take effect faster and are better tolerated with regard to
`The therapeutic effect might be greater and set in faster than with
`gastrointestinal side effects than orally administered tetracyclines,
`metronidazole alone (Fowler, 2007, poster presented at: American metronidazole and ketoconazole. In several smaller studies, both
`Academy of Dermatology 65th Annual Meeting; February 2-6,
`have been found to be effective and tolerable drugs in the short-
`2007; Washington, DC). Yet reliable data are not available as to
`term therapy of rosacea.52 54 After a 12-week treatment with
`whether the effectiveness of the combination is better than that of
`azithromycin in decreasing doses, there was a 75% decrease in
`total scores and an 89% decrease in inflammatory lesion scores
`anti-inflammatory dose doxycycline alone,
`
`19
`
`52
`
`JEADV2009, 23,876-882
`
`© 2009 The Authors
`Journal compilation © 2009 European Academy of Dermatology and Venereology
`
`5 of 7
`
`

`

`Approaches to treatment of rosacea
`
`881
`
`compared with basal values.54 According to a trial with a 3-year Both allow for a safe and effective short-term treatment of
`follow-up, rosacea patients that were treated with clarithromycin
`papulopustular rosacea, whereby azelaic acid has a slight
`required a significantly shorter treatment period (10.2 weeks) than
`advantage with regard to efficacy, and metronidazole with regard
`patients who received an antibiotic effective dose (200 mg per
`to tolerability. Among systemic drugs, low-dose non-antibiotic
`day) of doxycycline.52 Controlled clinical trials are necessary to
`doxycycline, especially with the once daily application approach,
`further elucidate the role of second-generation macrolides in both
`is the most interesting and, based on recent studies, the best
`short-term and, in particular, long-term therapy for rosacea,
`supported therapy option. Fortunately, it can also be used as a
`therapy on a long-term basis. Currently, no criteria exist for
`[~so~t÷~tir~oir~
`determining under which conditions preference should be made
`for topical or systemic therapy strategies. Since 2006, that is, since
`Isotretinoin is one of the few drugs which elicit a response with
`10
`once daily, non-antibiotic dose doxycycline is available in the
`several subtypes ofrosacea, but the quality of studies concerning
`this matter is generally very poor. Only small trials of low quality USA, there seems to be a trend to move towards using the systemic
`are available, whether randomized nor blinded, whose results
`therapy with doxycycline as first line monotherapy and not to
`have to be interpreted very carefully. In one of these small studies,
`reserve it for those patients only who did not experience success
`isotretinoin was effective for both erythematotelangiectatic and with topical therapy. Further studies must show whether
`papulopustular rosacea, including a reduced facial cutaneous
`combination therapies (e.g. with oral non-antibiotic dose
`blood flow in the isotretinoin group but not in the comparison
`doxycycline and topical metronidazole) lead to a further increase
`in efficacy in rosacea - what should indeed meet the expectations
`group treated with oxytetracycline (Irvine et al., as cited in
`Baldwin1°). Another study on 22 patients shows the effectiveness
`of at least a remarkable subgroup of bothered patients.
`of a 4-month low-dose isotretinoin therapy (10 mg per day) in
`patients with therapy-resistant rosacea. The treatment led to a R÷f;~regoes
`1 Bkiunt BW, Pelletier AP. Rosacea: a common yet commonly overlooked
`reduction of inflammatory lesions, erythema and telangiectasia.19
`condition. Am Fam Physician 2002; 66: 435 440,442.
`Overall the effect of isotretinoin therapy was delayed in
`2 Eiseman AS. The ocular manifestations of atopic dermatitis and rosacea.
`1855
`comparison to therapy with oral antibiotics. ’
`CurrAllergyAsthmaRep 2006; 6:292 298.
`3 Berg M, Liden S. An epidemiological study ofrosacea. 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,
`PaganaG. Epidemiologicaspectsofrosacea.JAmAcadDermato12005;53:
`918 919.
`6 DelRossoJQ, WebsterGF, KacksonMetal. Two randomized phase III
`clinical trials evaluating anti inflammatory dose doxycycline (40 mg
`doxycycline, USP capsules) administered once daily for treatment of
`rosacea. JAm Acad Dermato12007; 56:791 802.
`7 Feldman SR, Hollar CB, Gupta AK, Fleischer AB Jr. Women commonly
`seekcareforrosacea:dermatokigistsfrequentlyprovidethecare. Cutis2001;
`68:156 160.
`8 Berg M. Facial skin complaints and work at visual display units.
`Epidemiological, clinical and histopathological studies. Acta Derm Venereol
`1989; 150:1 40.
`9 Guttman C. Rosacea prevalence underestimated [WWW document] 2006.
`URL: http://www.modernmedicine.com/modernmedicine/
`Clinical+Dermatology/Rosacea prevalence underestimated/
`ArticleStandardArticle/detail/383156 (last accessed 23 May 2009).
`10 Baldwin HE. Systemic therapy for rosacea. Skin Therapy Lett 2007; 12:1 5.
`11 Millikan L. The proposed inflammatory pathophysiology of rosacea:
`implications for treatment. Skinmed 2003; 2:43 47.
`12 Bikowski J. Examining inflammation as a common factor in theories of
`rosacea pathophysiology [WWW document] 2008. URL
`www.rosaceatoday.com/TheoriesofRosacea.asp (last accessed 5 May
`2009).
`
`~,8÷tror~idaz©le
`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 200mg oral metronidazole significantly reduced papules
`56
`and pustules in 29 patients. A randomized study investigated the
`effectiveness of oral metronidazole (200mg twice daily) o