JEADV (2005) 19,273-285
`DOl: 10.1111/j.l468-3083.2005.01216.x
`
`Rosacea and its management: an overview
`
`AK Gupta,*t:t: MM Chaudhry:t:
`t Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Science Center (Sunnybrook site) and the University of
`Toronto, Toronto, Canada, :j:Mediprobe Research Inc., London, Ontario, Canada, *Corresponding author: 645 Windermere Road, London, Ontario,
`Canada N5X 2P1, tel. (519) 657-4222; fax (519) 657-4233; E-mail: agupta@execulink.com
`
`ABSTRACT
`Background Rosacea is a chronic inflammatory disorder that affects 10% of the population. The prevalence
`of rosacea is highest among fair-skinned individuals, particularly those of Celtic and northern European
`descent. Since a cure for rosacea does not yet exist, management and treatment regimens are designed to
`suppress the inflammatory lesions, erythema, and to a lesser extent, the telangiectasia involved with rosacea.
`Objectives This review outlines the treatment options that are available to patients with rosacea.
`Methods Published literature involving the treatment or management of rosacea was examined and summarized.
`Results Patients who find that they blush and flush frequently, or have a family history of rosacea are
`advised to avoid the physiological and environmental stimuli that can cause increased facial redness. Topical
`agents such as metronidazole, azelaic acid cream or sulfur preparations are effective in managing rosacea.
`Patients who have progressed to erythematotelangiectatic and papulopustular rosacea may benefit from the
`use of an oral antibiotic, such as tetracycline, and in severe or recalcitrant cases, isotretinoin to bring the
`rosacea flare-up under control. Treatment with a topical agent, such as metronidazole, may help maintain
`remission. Patients with ocular involvement may benefit from a long-term course of an antibiotic and the
`use of metronidazole gel. A surgical alternative, laser therapy, is recommended for the treatment of tel-
`angiectasias and rhinophyma. Patients with distraught feelings due to their rosacea may consider cosmetic
`camouflage to cover the signs of rosacea.
`Conclusions With the wide variety of oral and topical agents available for the effective management of
`rosacea, patients no longer need to feel self-conscious because of their disorder.
`Key words: azelaic acid, isotretinoin, management, metronidazole, rosacea, tetracycline
`
`Received: 17 September 2003, accepted: 13 April2004
`
`Background
`Rosacea is a chronic disorder, involving the mid facial region,
`and occasionally the neck and scalp and eyes,! It may progress
`from inflammatory lesions and/or erythema, to telangiectasia
`and rhinophyma, and sometimes also cause ocular involve-
`ment. The prevalence of rosacea is highest among fair-skinned
`individuals, especially those of Celtic and northern and eastern
`European heritage.2 The onset of rosacea is usually between
`the ages of 20 and 50 years, with females more often affected
`than males; however, males more frequently progress to the end-
`stages of severe rosacea. Rosacea has been described as having
`four subtypes, erythematotelangiectatic rosacea, papulopustular
`rosacea, phymatous rosacea, and ocular rosacea, with one
`variant, granulomatous rosacea.3
`
`© 2005 European Academy of Dermatology and Venereology
`
`Presently there is no cure for rosacea; management and treat-
`ment may provide only a method of suppressing its signs and
`symptoms. The choice of treatment is dependent primarily on
`the severity of the disorder and ranges from avoiding the factors
`that can trigger a flare-up, to the use of surgery for correcting
`the hypertrophied soft tissue of the nose (rhinophyma). This
`paper will discuss the treatment options rosacea patients have
`for managing their disorder.
`
`Pre-rosacea (episodic erythema)
`
`Avoidance policy
`The earliest manifestation of rosacea includes frequent flushing
`and blushing, or episodic erythema. Patients, who experience
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1044
`
`

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`REV IEW AR TICLE
`
`19, 273–285
`
`JEADV (2005)
`
`DOI: 10.1111/j.1468-3083.2005.01216.x
`
`Blackwell Publishing, Ltd.
`
`Rosacea and its management: an overview
`
`AK Gupta,*†‡ MM Chaudhry‡
`
`†Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook site) and the University of
`Toronto, Toronto, Canada,
`
`‡Mediprobe Research Inc., London, Ontario, Canada,
`
`*Corresponding author: 645 Windermere Road, London, Ontario,
`Canada N5X 2P1, tel. (519) 657-4222; fax (519) 657-4233; E-mail: agupta@execulink.com
`
`ABSTRACT
`Background
`Rosacea is a chronic inflammatory disorder that affects 10% of the population. The prevalence
`of rosacea is highest among fair-skinned individuals, particularly those of Celtic and northern European
`descent. Since a cure for rosacea does not yet exist, management and treatment regimens are designed to
`suppress the inflammatory lesions, erythema, and to a lesser extent, the telangiectasia involved with rosacea.
`Objectives
`This review outlines the treatment options that are available to patients with rosacea.
`Methods
`Published literature involving the treatment or management of rosacea was examined and summarized.
`Results
`Patients who find that they blush and flush frequently, or have a family history of rosacea are
`advised to avoid the physiological and environmental stimuli that can cause increased facial redness. Topical
`agents such as metronidazole, azelaic acid cream or sulfur preparations are effective in managing rosacea.
`Patients who have progressed to erythematotelangiectatic and papulopustular rosacea may benefit from the
`use of an oral antibiotic, such as tetracycline, and in severe or recalcitrant cases, isotretinoin to bring the
`rosacea flare-up under control. Treatment with a topical agent, such as metronidazole, may help maintain
`remission. Patients with ocular involvement may benefit from a long-term course of an antibiotic and the
`use of metronidazole gel. A surgical alternative, laser therapy, is recommended for the treatment of tel-
`angiectasias and rhinophyma. Patients with distraught feelings due to their rosacea may consider cosmetic
`camouflage to cover the signs of rosacea.
`Conclusions
`With the wide variety of oral and topical agents available for the effective management of
`rosacea, patients no longer need to feel self-conscious because of their disorder.
`Key words:
`azelaic acid, isotretinoin, management, metronidazole, rosacea, tetracycline
`
`Received: 17 September 2003, accepted: 13 April 2004
`
`Background
`Rosacea is a chronic disorder, involving the mid facial region,
`and occasionally the neck and scalp and eyes.
` It may progress
`1
`from inflammatory lesions and/or erythema, to telangiectasia
`and rhinophyma, and sometimes also cause ocular involve-
`ment. The prevalence of rosacea is highest among fair-skinned
`individuals, especially those of Celtic and northern and eastern
`European heritage.
` The onset of rosacea is usually between
`2
`the ages of 20 and 50 years, with females more often affected
`than males; however, males more frequently progress to the end-
`stages of severe rosacea. Rosacea has been described as having
`four subtypes, erythematotelangiectatic rosacea, papulopustular
`rosacea, phymatous rosacea, and ocular rosacea, with one
`variant, granulomatous rosacea.
`3
`
`Presently there is no cure for rosacea; management and treat-
`ment may provide only a method of suppressing its signs and
`symptoms. The choice of treatment is dependent primarily on
`the severity of the disorder and ranges from avoiding the factors
`that can trigger a flare-up, to the use of surgery for correcting
`the hypertrophied soft tissue of the nose (rhinophyma). This
`paper will discuss the treatment options rosacea patients have
`for managing their disorder.
`
`Pre-rosacea (episodic erythema)
`
`Avoidance policy
`
`The earliest manifestation of rosacea includes frequent flushing
`and blushing, or episodic erythema. Patients, who experience
`
`© 2005 European Academy of Dermatology and Venereology
`
`273
`
`Exh. 1044
`
`

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`
`274
`
`Gupta and Chaudhry
`
`Table 1 Rosacea trigger factors and management techniques
`
`Rosacea triggering factors
`
`Management factors
`
`Foods:
`Meat: liver
`Dairy products: yogurt, sour cream, cheeses (not including cottage cheese)
`Vegetables: eggplant, tomatoes, spinach, lima and navy beans, peas
`Fruits: avocados, bananas, red plums, raisins, figs, and citrus fruits
`Condiments/flavoring: chocolate and vanilla, soy sauce and vinegars
`Other: hot and spicy foods, yeast extraction
`
`Beverages:
`Alcohol and hot beverages
`
`Emotional:
`Stress and anxiety
`
`Weather:
`Sun, strong winds, cold, humidity
`
`Temperature:
`Any hot environment: saunas, hot baths, simple overheating
`
`Skin Care Products:
`Cosmetics and hairsprays especially those containing alcohol, witch hazel or fragrances
`Hydro-alcoholic or acetone substances
`Any substance that causes redness or stinging
`
`Medications:
`Vasodilators, and topical steroids
`
`Medical Conditions:
`Menopause, caffeine withdrawal syndrome, chronic cough,
`frequent flushing
`
`Physical Exertion:
`Exercise, heavy lifting
`
`Identify and avoid any foods that aggravate the condition
`
`Avoid alcoholic beverages, especially red wine, beer,
`bourbon, gin, vodka or champagne
`Avoid hot drinks, e.g. Tea, coffee, hot cider or hot chocolate
`
`Practice stress management techniques, e.g. Yoga or
`breathing exercises
`
`Use ski masks, scarves to protect from cold and windy
`conditions
`Use sunscreens (min. SPF 15)
`
`Avoid any hot or humid environment
`
`Resist using skin products that are listed as irritating
`
`If avoidance is not possible, they should not be taken for
`long periods of time
`
`Not avoidable; however, avoiding other factors minimizes
`these conditions
`
`Avoid long strenuous exercising and heavy lifting
`Use cool-down techniques: chewing on ice, or covering face
`with cool cloth after the workout
`
`frequent blushing, have a family history of rosacea, or both may
`be entering prerosacea; these patients are advised to consider
`changing their lifestyle to control their blushing. The best
`approach to preventing the blushing and flushing associ-
`ated with the stages of rosacea is the avoidance policy,
`4
`where nonspecific physiological and environmental stimuli are
`avoided, and thus increased facial redness is lessened. One study
`reported 78% of rosacea patients felt that avoiding the factors
`that aggravate their rosacea was effective or at least somewhat
`effective in controlling their condition.
` The most common
`5
`triggers of blushing include alcohol ingestion, spicy food, sun
`exposure, or stress. However, the causes may vary from patient
`to patient, and therefore it is important for a patient to avoid
`these causative agents as much as possible during their daily
`routine. Physicians of rosacea patients must be aware that
`rosacea is a recognized and controllable disorder; they should
`educate and monitor their patients for possible triggers and try
`to establish an individual risk factor profile.
` Table 1 outlines
`6
`
`some common factors that may trigger and aggravate rosacea
`flare-ups.
`
`Drug therapy
`
`Drug treatment trials for decreasing the flushing associated
`with rosacea have primarily been unsuccessful. Two drugs,
`clonidine and nadolol have been tried against rosacea flushing;
`neither was effective. One study demonstrated that twice-daily
`treatment with clonidine hydrochloride, 0.05 mg, taken for 2
`weeks was unable to suppress the flushing reactions provoked
`°
`with hot water (60
`C), red wine and chocolate in 23 of 24
`patients with erythematotelangiectatic rosacea.
` Similarly,
`7
`treatment with 40 mg of nadolol once or twice daily had no
`°
`apparent effect on flushing induced by hot water (60
`C), ethanol,
`and niacin in 15 patients with erythematous telangiectatic
`rosacea.
` However, one double-blind study showed that
`8
`10-minute pretreatment with naloxone 0.8 mg in 2 mL saline
`
`© 2005 European Academy of Dermatology and Venereology
`
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`JEADV (2005) 19, 273–285
`
`Exh. 1044
`
`

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`injected subcutaneously completely inhibited alcohol induced
`facial flushing in all five subjects.
` The mean forehead skin
`9
`±
`°
`temperature increased by 1.1
` 0.6
`C during flushing
`±
`°
`after saline administration, but by only 0.4
` 0.2
`C after
`naloxone administration. Currently, there are no effective
`long-term drug therapies to control the flushing associated
`with rosacea.
`
`Erythematotelangiectatic and
`papulopustular rosacea
`Rosacea is a progressive disorder, and although not all pati-
`ents necessarily pass through all stages, early diagnosis and
`management will prevent or lessen the chances that the rosacea
`will worsen. A variety of oral and topical treatments, with the
`ability of suppressing the disorder, are available for patients
`suffering with rosacea.
`
`Systemic therapy
`
`Several oral agents have been used in the treatment of rosacea.
`Table 2 summarizes the clinical trials evaluating the efficacy of
`these systemic drugs.
`
`Oral antibiotics
`
`Oral antibiotics have long been accepted as safe and effective
`treatments for rosacea, and are thought to exert their
`therapeutic effects primarily via anti-inflammatory rather than
`antibacterial methods. Antibiotic therapy is most effective
`against inflammatory papules and pustules, with minimal
`effects on erythema and telangiectasia.
`26
`Tetracycline has historically been the antibiotic of choice for
`treating rosacea, as it has been shown to be successful in reduc-
`ing the number of papules and pustules. High doses are initially
`recommended until the disorder is brought under control,
`and then lower doses are used to maintain control. Total daily
`doses of up to 1000 mg, taken two to four times a day are
`recommended for up to 4 weeks, and then reduced by half for
`an additional 5 months.
`Tetracycline has proven to be successful in treating patients
`diagnosed with rosacea. In one randomized, double-blind
`study, 78% of patients treated with tetracycline 250 mg twice
`daily for 1 month experienced the disappearance of pustules,
`the flattening of papules and the diminution of erythema.
` In
`11
`another randomized, double-blind clinical trial, compared with
`ampicillin, tetracycline 250 mg taken three times daily for the
`first week and then twice daily for the subsequent 5 weeks, did
`not significantly differ in the reduction of papules and pustules;
`however, post-treatment evaluation revealed that both treat-
`ments were effective in decreasing the mean number of papules
`and pustules in comparison with the pretreatment means
`
`P < 0.05).
`(
`12
`
`Management of rosacea
`
`275
`
`The effects of doxycycline, 100 mg twice daily for 4 weeks,
`then once daily for another 4 weeks were compared with clari-
`thromycin, 250 mg twice daily for 4 weeks, then once daily for
`another 4 weeks in patients with mild and moderate rosacea.
`13
`The overall results of the treatment provide evidence of a higher
`clarithromycin efficacy profile in comparison with doxycycline.
`Significant differences were seen in erythema in favour of the
`
`
`clarithromycin group at weeks 4 and 6 (P < 0.05); however,
`after 8 weeks of treatment, no significant differences were seen
`in erythema. A significant difference between the mean values
`of the numbers and dimensions of telangiectasia in the two
`groups of patients was observed after 4 weeks of treatment.
`After 6 and 8 weeks of treatment, there were no significant dif-
`ferences between the two groups. A significantly faster decrease
`
`P < 0.0005) of the mean number of papules and pustules was
`(
`observed in the clarithromycin-treated patients, when com-
`pared with the doxycycline-treated patients after 4 and 6 weeks
`of therapy; however, after 8 weeks there was no significant dif-
`ference in these two parameters between the two groups.
`Treatment with antibiotics must be long-term, lasting a
`minimum of 6 months. Treatment failure with antibiotics is most
`commonly the result of patient noncompliance, particularly
`resulting from side-effects including nausea, and also because
`some antibiotics, such as tetracycline must been taken on an
`empty stomach; food and milk restrict its absorption.
`
`Oral metronidazole
`
`Oral metronidazole is a treatment alternative for rosacea
`patients who do not respond well to tetracycline. Two double-
`blind, randomized controlled trials assessed the efficacy of oral
`metronidazole.
` Metronidazole 200 mg, taken twice daily for
`14,15
`12 weeks proved to be as effective as oxytetracycline 250 mg
`taken twice daily in improving the papulo-pustules related to
`rosacea.
` In addition, 6 weeks of therapy with metronidazole
`14
`200 mg taken twice daily in combination with 1% hydrocortisone,
`applied twice daily produced ‘definite improvement’ in the overall
`clinical severity of the rosacea condition in 10 of 14 patients.
`15
`
`Isotretinoin
`
`Another effective therapy in the treatment of rosacea is
`isotretinoin. However, this treatment is suggested for patients
`with severe or recalcitrant rosacea. Patients may benefit from
`a trial with systemic tetracycline, metronidazole or topical
`metronidazole before the use of isotretinoin. Daily doses of
`isotretinoin usually range from 0.5 mg/kg to 1.0 mg/kg. The
`advantage of isotretinoin is that it has an immediate effect on
`papules and pustules. Four studies have shown isotretinoin to
`significantly decrease the mean number of papules and pustules
`compared to baseline
` within as little as 1 month of
`17–20
` Isotretinoin also produces considerable improve-
`therapy.
`18
`ment in erythema,
` however, the effects may be slow and
`17,20
`
`© 2005 European Academy of Dermatology and Venereology
`
`
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`JEADV (2005) 19, 273–285
`
`Exh. 1044
`
`

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`
`276
`
`Gupta and Chaudhry
`
`Erythema
`
`Telangiectasia
`
`Physician
`assessment
`
`Patient
`assessment
`
`No significant
`difference
`
`No significant difference
`
`Improvement in
`clindamycin: 94.7%
`of patients
`tetracycline:
`94.4% of patients
`
`Improvement seen in
`81.8% of patients
`treated with
`clindamycin and
`90.5% of tetracycline
`
`Other
`
`N/A
`
`Reference
`
`Wilkin 1993
`10
`
`Table 2
`
`Systemic therapies used in the treatment of rosacea
`
`Study design
`
`Regimen
`
`DB, R 1% clindamycin
`phosphate lotion vs.
`oral tetracycline
`=
`
`N
` 43; 12 weeks
`
`1% clindamycin lotion
`+
` placebo or
`b.i.d.
`250 mg tetracycline q.i.d.
`+
` placebo lotion for
`9 weeks
`
`Efficacy parameters
`Inflammatory
`lesions
`
`Clindamycin: facial
`lesions decreased
`from baseline
`<
`(
`
`P
` 0.05)
`tetracycline: facial
`lesions decreased
`from baseline
`<
`(
`
`P
` 0.05)
`
`DB, R Tetracycline vs.
`=
`placebo
`
`N
` 78;
`4 weeks
`
`Tetracycline 250 mg
`b.i.d. or placebo tablets
`b.i.d. for 4 weeks
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`Sneddon 1966
`11
`
`Improvement in
`disappearance of
`pustules, flattening of
`papules, and diminution
`of erythema:
`Tetracycline: 78%
`Placebo: 45%
`
`DB, R Tetracycline vs.
`=
`ampicillin
`
`N
` 56;
`6 weeks
`
`t.i.d. for the first week
`then b.i.d. for 5 weeks
`
`Tetracycline:
`decreased from
`21.05 to 4.6
`ampicillin:
`decreased from
`21.06 to 9.53
`
`No significant
`difference
`
`N/A
`
`N/A
`
`Ampicillin marginally
`better than tetracycline
`
`N/A
`
`Marks 1971
`12
`
`Clarithromycin
`=
`vs.doxycycline
`N
`
` 40;
`8 weeks
`
`Clarithromycin 250 mg
`b.i.d. for 4 weeks then
`q.i.d. for 4 weeks or
`doxycycline 100 mg b.i.d.
`for 4 weeks then q.i.d.
`for 4 weeks
`
`No significant
`difference between
`treatments after
`8 weeks
`
`No significant
`difference between
`treatments after
`8 weeks
`
`No significant difference
`between treatments after
`8 weeks
`
`No significant
`difference between
`treatments after
`8 weeks
`
`N/A
`
`Torresani 1997
`13
`
`DB, R Metronidazole
`vs. oxytetracycline
`=
`
`N
` 38; 12 weeks
`
`Metronidazole 200 mg
`b.i.d. or oxytetracycline
`250 mg b.i.d. 12 weeks
`
`N/A
`
`N/A
`
`N/A
`
`DB, R Metronidazole
`=
`vs. placebo
`
`N
` 27;
`6 weeks
`
`Metronidazole 200 mg
`+
`1%
`b.i.d.
`hydrocortisone cream
`+
`daily or placebo
`1%
`hydrocortisone for
`6 weeks
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`Saihan 1980
`14
`
`N/A
`
`N/A
`
`Pye 1976
`15
`
`Mean independent
`opinion of patient
`and 2 doctors
`No significant
`difference between
`groups; both
`improved from
`<
`baseline (
`
`P
` 0.05)
`
`10 patients in
`metronidazole and 2
`patients in placebo
`group showed good
`<
`results (
`
`P
` 0.02)
`
`© 2005 European Academy of Dermatology and Venereology
`
`JEADV
`
` (2005)
`
`19
`
`, 273–285
`
`Exh. 1044
`
`

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`
`Management of rosacea
`
`277
`
`Efficacy parameters
`Inflammatory
`lesions
`
`All groups showed
`significant difference
`from baseline
`<
`(
`
`P
` 0.01)
`
`Erythema
`
`Telangiectasia
`
`Physician
`assessment
`
`Patient
`assessment
`
`N/A
`
`N/A
`
`N/A
`
`Group 1: 41%
`reduction Group 2:
`27% reduction
`Group 3: 40%
`reduction
`
`Other
`
`N/A
`
`Reference
`
`Ertle 1994
`16
`
`Table 2 Continued
`
`Study design
`
`Regimen
`
`DB, R Isotretinoin vs.
`tretinoin cream vs.
`=
`combo
`
`N
` 20;
`32 weeks
`
`Group 1: isotretinoin 10
`+
` placebo cream for
`mg/d
`16 weeks then placebo
`cream for 16 weeks or
`Group 2: 0.025% tretinoin
`+
`cream
` placebo tablets
`for 16 weeks then tretinoin
`cream for 16 weeks or
`Group 3: combo
`(isotretinoin and tretinoin)
`+
` placebo tablets for
`16 weeks then tretinoin
`cream for 16 weeks
`
`Open label isotretinoin
`=
`
`N
` 92; 20 weeks
`
`Isotretinoin 0.5 mg/kg/
`bw
`
`Mean papules
`decreased from 42
`to 5 mean pustules
`decreased from 11 to
`0.6
`
`Improved
`considerably
`
`Improved considerably
`
`Number of patients
`with good or very
`good response: 64
`
`Number of patients
`fully or partially
`satisfied: 64
`
`Edema improved
`considerably
`
`Hoting 1986
`17
`
`Open label isotretinoin
`=
`
`N
` 20; 6 months
`
`Isotretinoin 0.5 mg/kg or
`1.0 mg/kg for 3 months
`
`N/A
`
`N/A
`
`N/A
`
`Open label isotretinoin
`=
`
`N
` 7; 20 weeks
`
`Isotretinoin 1.0 mg/kg/bw
`for 12 weeks
`
`Facial lesions
`decreased from 39.7
`to 4 at 6 weeks
`<
`(
`
`P
` 0.001) and rose
`to 10.6 at week 20
`
`N/A
`
`Measured by
`reflectometer.
`Decreased from
`10.8 units to 10.1
`units at 12 weeks
`then to 9.1 at week
`20
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`Turjanmaa 1987
`18
`
`Total clinical score
`(includes papules,
`pustules, erythema and
`oiliness): decreased from
`<
`7.5 to 1.25 (
`
`P
` 0.001)
`
`N/A
`
`Marsden 1984
`19
`
`Open label isotretinoin
`=
`
`N
` 18; 16 weeks
`
`Isotretinoin 1.0 mg/kg/bw
`for 16 weeks
`
`Significantly
`decreased from 8.86
`<
`to 2.55 (
`
`P
` 0.001)
`
`Significantly
`decreased
`<
`
`P
` 0.001)
`(
`
`Significantly decreased
`<
`
`P
` 0.001)
`(
`
`Erdogan 1998
`20
`
`DB, R Lemecycline vs.
`
`N = 37;
`sulphur
`4 weeks
`
`Lymecycline 150 mg 2
`capsules b.i.d. for 1 week
`then 1 capsule b.i.d. for 3
`weeks + placebo cream
`or 10% sulphur cream
`q.i.d. + placebo capsules
`for 4 weeks
`
`Sulphur: number
`decreased from 213
`to 17; Lymecycline:
`number decreased
`from 143 to 131
`
`No significant
`difference
`
`No significant difference No significant
`difference
`
`No significant
`difference
`
`N/A
`
`Blom 198421
`
`© 2005 European Academy of Dermatology and Venereology
`
`JEADV
`
` (2005)
`
`19
`
`, 273–285
`
`Exh. 1044
`
`

`
`278 Gupta and Chaudhry
`
`Erythema
`
`Telangiectasia
`
`Physician
`assessment
`
`Patient
`assessment
`
`N/A
`
`Metronidazole:
`decreased from 2.5
`to 1.1
`Oxytetracycline:
`decreased from 2.4
`to 1.1; No
`significant
`difference
`
`Definite improvement
`in 75% of
`metronidazole treated
`patients and 80% of
`oxytetracycline
`treated patients
`
`Definite improvement
`in 67% of
`metronidazole treated
`patients and 80% of
`oxytetracycline treated
`patients
`
`Other
`
`N/A
`
`Reference
`
`Monk 199122
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`Weien 198623
`
`Significant
`reduction from
`baseline. No
`significant
`difference between
`treatments
`
`Reduction from
`baseline;
`No significant
`difference between
`groups
`
`Number and extent of
`telangiectasia remained
`unchanged;
`No significant difference
`
`Improved patients:
`metronidazole: 96%
`oxytetracycline: 96%;
`No significant
`difference
`
`Improved patients:
`metronidazole: 88%
`oxytetracycline: 91%;
`No significant
`difference
`
`Nielson 198324
`
`Photographic
`evaluation Improved
`patients:
`metronidazole:
`84% oxytetracycline:
`91%; No significant
`difference
`
`No differences in
`degree of erythema
`compared to
`baseline
`
`No differences noted in
`degree of telangiectasia
`compared to baseline
`
`N/A
`
`Both groups showed
`much improvement
`
`N/A
`
`Schachter 199125
`
`Table 2 Continued
`
`Study design
`
`Regimen
`
`DB, R Oxytetracycline
`vs. metronidazole
`N = 27; 9 weeks
`
`Oxytetracycline 250 mg
`bid + placebo cream vs.
`Metronidazole 0.75% gel
`b.i.d. + placebo tablets
`for 9 weeks
`
`DB, R Tetracycline vs.
`metronidazole N = 75;
`8 weeks
`
`Tetracycline 250 mg
`b.i.d. + placebo cream or
`Metronidazole 1% cream
`q.i.d. for 8 weeks
`
`DB, R Oxytetracycline
`vs. metronidazole
`N = 48; 2 months
`
`Oxytetracycline 250 mg
`b.i.d. + placebo cream or
`metronidazole 1% cream
`q.i.d. + placebo tablets
`for 2 months
`
`DB, R Tetracycline vs.
`metronidazole
`N = 101; 2 months
`
`Tetracycline 250 mg t.i.d.
`+ placebo cream or
`Metronidazole 1% cream
`q.i.d. for 2 months
`
`Efficacy parameters
`Inflammatory
`lesions
`
`Facial lesions
`decreased 100% in
`75% of the
`Metronidazole-
`treated patients and
`in 66% of
`oxytetracycline-
`treated patients; No
`significant
`difference
`
`Significantly more
`patients treated with
`tetracycline obtained
`100% reduction of
`papules and
`pustules; No
`significant difference
`between treatments
`
`Reduction from
`baseline; No
`significant difference
`between groups
`
`Significantly fewer
`number of papules
`and pustules from
`baseline (P < 0.05)
`papule decrease:
`metronidazole: 68%
`tetracycline: 77%
`pustule decrease:
`metronidazole: 68%
`tetracycline: 77%
`
`q.i.d., once daily; b.i.d., twice daily; t.i.d., thrice daily; DB, double-blind; R, random; N, number of patient.
`
`© 2005 European Academy of Dermatology and Venereology JEADV (2005) 19, 273–285
`
`Exh. 1044
`
`

`
`incomplete.18 In addition, patients may remain in remission
`for at least 1 year after discontinuing treatment.18
`One study performed ophthalmologic examinations in patients
`taking isotretinoin.17 Blepharitis and conjunctivitis, which are
`quite common symptoms in patients with rosacea, were present
`in 23 of 88 and 33 of 88 subjects, respectively, which decreased,
`respectively, to 17 of 54 and 25 of 54 subjects at week 20.
`Although isotretinoin has been demonstrated to be effective
`in treating the papules and pustules associated with rosacea,
`considerable drug intolerance is seen. The most common side-
`effects that occur with isotretinoin are mucosal, such as dryness
`of the lips and nose. Other side-effects that may be seen are
`cheilitis, dermatitis, musculoskeletal pain, tinnitus, headache,
`and an increase in triglyceride levels. The number and extent of
`these side-effects may be the limiting factors to this form of
`therapy for rosacea treatment.
`
`Topical treatments
`
`Metronidazole 1% cream, Metronidazole 0.75% gel,
`lotion and cream
`
`Topical metronidazole, available either as a gel or a cream, is the
`most popular topical agent for treating rosacea. Metronidazole
`0.75% gel22,27–29 and metronidazole 1% cream,14,23,25,30–37
`metronidazole 0.75% cream35,38 and metronidazole lotion39
`have been shown to be effective in treating rosacea when applied
`once or twice daily for 8–12 weeks. The results of these studies
`have demonstrated that both preparations significantly decrease
`the number of inflammatory lesions and reduce the erythema
`associated with rosacea. In addition, neither the cream nor
`the gel seemed to have an effect on the telangiectasia. How-
`ever, Tan 2001,36 reported that metronidazole 1% cream with
`sunscreen SPF 15 significantly decreased facial telangiectasia
`(P = 0.043).
`Studies that have compared 1% metronidazole cream with
`tetracycline have found that although the end result shows no
`significant difference between topical metronidazole and tetra-
`cycline, tetracycline does have a faster onset than metronida-
`zole.23–25 In addition, other studies have shown that following
`tetracycline withdrawal, the relapse rate is high. These findings
`suggest that the use of a topical agent following systemic therapy
`might be beneficial in preventing relapse after the oral agent is
`discontinued.
`
`Other topical therapies
`
`As a result of the positive effects of topical metronidazole,
`several other studies have evaluated the outcome of other
`topical agents in treating rosacea. Topical alternatives to
`metronidazole include: 1% clindamycin phosphate lotion,10
`topical tretinoin,16 and 5% permethrin cream.40,41 The effective-
`ness of these topical agents has been compared to proven,
`
`Management of rosacea 279
`
`successful systemic and topical therapies. When 1% topical
`clindamycin phosphate lotion was compared with tetracycline,10
`clindamycin phosphate reduced the mean number of pustules,
`papules, and nodules while tetracycline significantly reduced
`only papule and nodule counts from baseline. Comparison
`of topical tretinoin with isotretinoin16 revealed that both
`treatments were effective in decreasing the number of papules,
`pustules and erythema after 16 weeks of treatment, with no
`significant difference between the two treatment groups in
`papules and pustules. The results of 5% permethrin cream
`compared to 0.75% metronidazole gel showed that both
`treatments produced gradual improvement in erythema and
`papules.40,41
`The efficacy of two other topical preparations, sodium sul-
`facetamide 10%/sulphur 5% lotion42,43 and 10% sulphur cream21
`were also evaluated in the treatment of rosacea. Both pre-
`parations proved to be effective in decreasing the number of
`papules and pustules in patients. The sodium sulfacetamide
`10%/sulphur 5% lotion demonstrated significant reduction
`in erythema.42,43
`Another topical agent, 0.05% retinaldehyde cream was found
`to have beneficial effects on the vascular component of rosa-
`cea.44 In an open-labelled study, 23 females with rosacea applied
`retinaldehyde 0.05% once daily for 6 months. Clinical response
`was obtained in approximately 75% of patients with erythema
`after 5 months of treatment (P < 0.05).
`The antimicrobial, comedolytic and anti-inflammatory
`activity of azelaic acid 20% cream has been shown to be benefi-
`cial in the treatment of rosacea. Two studies that evaluated the
`efficacy and safety of azelaic acid 20% cream recorded that this
`agent produced significantly greater mean reductions in the
`number of papules, pustules and erythema than vehicle.45,46
`Following twice-daily application of azelaic acid 20% cream,
`the mean number of papules and pustules decreased from 14.2
`to 2.5 after 9 weeks of treatment,45 and from 30.8 to 8.3 after
`3 months of treatment.46 Furthermore, Carmichael45 found the
`erythema index decreased from 539.6 ± 13.4 to 500.6 ± 14.7
`after 9 weeks of treatment. Bjerke46 found the erythema severity
`score reduced by 47.9%. In addition, another study found
`twice-daily applications of azelaic acid 20% cream to be equi-
`valent to twice-daily applications of metronidazole 0.75% cream
`in the treatment of inflammatory lesions, with no significant
`difference in efficacy between the two groups.38
`In addition to the azelaic acid cream treatments, recently,
`there has been investigation into a lower concentration (15%)
`azelaic acid gel (AzA gel) as a new treatment for papulopustular
`rosacea through two vehicle-controlled, randomized studies.47
`The study found that the AzA gel group yielded a statistically
`significantly higher reduction in mean inflammatory lesion
`count than its vehicle in both study 1 (P = 0.0001) and study 2
`(P = 0.0208), with a reduction in 58% and 51%, respectively.
`This study also found that a significantly higher proportion of
`patients treated with AzA gel experienced improvement in
`
`© 2005 European Academy of Dermatology and Venereology JEADV (2005) 19, 273–285
`
`Exh. 1044
`
`

`
`280 Gupta and Chaudhry
`
`erythema when compared with the vehicle. In study 1, improve-
`ment of erythema severity was seen in 44% of patients in the
`AzA group, compared to only 29% of the vehicle group
`(P = 0.0017). Study 2, showed improvement in 46% of patients,
`while only 28% of the vehicle group improved (P = 0.0005).
`Furthermore, the study found that there were no serious treatment-
`related adverse events, and the final conclusion of the investig-
`ators was that AzA gel, used twice daily, is an efficacious, safe, and
`well-tolerated topical treatment for moderate, papulopustular
`rosacea.47
`All these topical preparations have demonstrated efficacy in
`the treatment of papules, pustules and to a certain exte