The NEW ENGLAND JOURNAL of MEDICINE
`
`CLINICAL PRACTICE
`
`]
`
`Rosaeea
`
`Frank C. Powell, F.R.C.P.I.
`
`This Journal feature begins with a case vignette highlighting a common clinical problem.
`Evidence supporting various strategies is then presented,followed by a review of formaI guideIines,
`when they exist. The article ends with the author’s clinical recommendations.
`
`A 47-year-old white woman reports facial redness and flushing. Her eyes are itchy and
`irritated. She thinks she may have rosacea and is worried that she will have a"whiskey
`nose." On examination, multiple erythematous papules, pustules, and telangiectasias
`are observed on a background of erythema of the central portion of her face. How
`should her case be managed?
`
`THE CLINICAL PROBLEM
`
`A constellation ofclinical symptoms and signs are included under the broad rubric of From the Regional Centre of Dermatology,
`rosacea. These consist of facial flushing, the appearance oftelangiectatic vessels and Mater Misericordiae Hospital, Dublin. Send
`reprint requests to Dr. Powell at the Region-
`persistent redness of the face, eruption of inflammatory papules and pustules on the
`al Centre of Dermatology, Mater Misericor-
`central facial convexities, and hypertrophy of the sebaceous glands of the nose, with fi-
`diae Hospital, Eccles St., Dublin 7, Ireland,
`brosis (rhinophyma).~ Ocular changes are present in more than 50 percent ofpatients or at fpowell@eircom.net.
`and range from mild dryness and irritation with blepharitis and conjunctivitis (common N E ngl J Med 2005;352: 793-803.
`symptoms) to sight-threatening keratitis (rare).2 Patients with rosacea may report in-
`copyr~eh~ © 2oos M~ss~ch~se~s Mea~c~ So~y
`creased sensitivity of the facial skin3 and may have dry, flaking facial dermatitis, edema
`of the upper face,4 or persistent granulomatous papulonodules.5 There is often an over-
`lapping of clinical features, but in the majority of patients, a particular manifestation of
`rosacea dominates the clinical picture. As a useful approach to the guidance of therapy,
`the disease can thus be classified into four subtypes -- erythematotelangiectatic (sub-
`type 1), papulopustular (2), phymatous (3), and ocular (4)6 --with the severity of each
`subtype graded as 1 (mild), 2 (moderate), or 3 (severe).7 The psychological, social, and
`occupational effects of the disease on the patient should also be assessed and factored
`into treatment decisions.
`The onset of rosacea usually occurs between the ages of 30 and 50 years.8 The
`course of the disease is typically chronic, with remissions and relapses. Some patients
`identify exacerbating factors, particularly in regard to flushing, such as heat, alcohol,
`sunlight, hot beverages, stress, menstruation, certain medications, and certain foods?
`Rosacea is more common in women than in men, but men with rosacea are more prone
`to the development of thickening and distorting phymatous skin changes. Rosacea has
`been anecdotally reported to be associated with seborrheic dermatitis (this association
`is likely), with migraine headaches in women~° (possible), and with Helicobacter pylori in-
`fection~ (controversial). A rosacea-like eruption can be induced by the topical applica-
`tion of fluorinated corticosteroids~2 and tacrolimus ointment~3 to the face. In two Eu-
`ropean population studies, the prevalence ofrosacea was reported to be 1.5 percent~4
`and 10 percent,~s but estimates are complicated by the difficulty of distinguishing be-
`tween chronic actinic damage and erythematotelangiectatic rosacea. Although rosacea
`can occur in all racial and ethnic groups, white persons of Celtic origin are thought to be
`particularly prone to the disorder,~6 and it is uncommon in persons with dark skin. Up to
`30 percent of patients report a family history ofrosacea.~7 The common misconception
`
`N ENGL J MED 352;8 WWW. NEJM.ORG FEBRUARY 24, 2005
`
`793
`
`The New England Journal of Medicine
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`Copyright © 2005 Massachusetts Medical Society. All rights reserved.
`
`1 of 11
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`Almirall EXHIBIT 2038
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`794
`
`N ENGL J MED 352;8 WWW. NEJM.ORG FEBRUARY 24, 2005
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ALLERGAN INC on September 24, 2018. For personal use only¯ No other uses without permission.
`Copyright © 2005 Massachusetts Medical Society¯ All rights reserved.
`
`2 ofll
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`

`

`CLINICAL PRACTICE
`
`STRATEGIES AND EVIDENCE
`
`~
`._
`~’ ~3~
`~ o ~ .-
`.... o
`.-= ~ = n =
`.._ oa
`oa
`E
`~ o~ ao ao
`~_o o~ E
`o oa
`v o ~ c ~
`o >-z ~m~:~c ~
`
`~.~_ ..... e
`
`~
`g ~
`
`oa "
`
`m~z
`
`v v o-O-~
`
`¯ ~_-
`
`o > >
`
`o ~ o o_
`
`o > o
`
`o o .-- ~ w
`~’-~ .~
`
`con ~n
`
`that both the facial redness and the rhinophyma as-
`n _o ~:
`~o_~_~
`sociated with rosacea are due to excessive alcohol
`~ E o g
`consumptionmal<esrosaceaasociallystigmatizing
`~o*~g
`condition for many patients.
`g ~~ ~ ~ =
`oa
`>--o
`~00
`o_ ~ ~ ~
`z-~
`=o.- - ~ ~ ~ ,.. The diagnosis ofrosacea is a clinical one. There is
`noconfirmatorylaboratorytest.Biopsyiswarranted
`~ ~ 8 ~ e
`only to rule out alternative diagnoses, since histo-
`o_.~ #_
`~o
`pathological findings are not diagnostic?8
`The differential diagnosis and therapy vary ac-
`~ ~ ~ = ~
`n = ~ -
`~>._~ =~
`cording to subtype (Table 1). Rosacea that is mani-
`~.~ nr_° .2 o°
`~o~ ~~ g ~
`~o ~_
`~ ~ o n ~
`fested predominantly by flushing is difficult to treat,
`._ o o
`but the condition may improve with the manage-
`~ ~ ~o ~ ~ =
`.8~~ ~ o
`.~ o~ o
`~ ~ ~ *g
`ment of other manifestations and the avoidance
`¯ ~ ~ o 8
`of provoking or triggering factors. Inflammatory
`changes in the skin are usually responsive to medi-
`~ 8_ ~.~ ~
`cal therapies and heal without scarring, whereas tel-
`_~ ~ .o ._= ~
`~ o "6 ~ g
`._~ ._~
`angiectasias and phymatous changes often require
`~
`laserorsurgicalintervention.Ocularrosaceaisusu-
`._.-=~° ~-
`~.~=- ~ ~
`.~ .g ~
`~ ~
`~ 8 ~ .~°
`o~ ~ ~,° o =
`
`.... .... allymild and responsive to lid hygiene, tear replace-
`~ .~ Vo "~= ~:°
`.~ ~= ~_~ ~ -~ ~ ~-
`~ ~ ~ 8 ~ ment, and topical or systemic antibiotics, but pa-
`~- ~ 8 8
`o~n~- ~_~ n~_.o o
`g~-~.~
`.
`~ ~:= o
`~ o-~ ~ ~
`tientswithpersistentorsevereoculardiseaseshould
`v~:
`~ o > .... .=
`~ ~ ~
`~ ~
`= ~’~ v
`~o
`~-.~ = = ~ _o ~ ~ .-
`¯ = ~_ g ~
`be referred to an ophthalmologist. All patients
`0"7"
`~ o
`a~’~ o
`.~_ m ._ ~
`. ~: oa .m ._m
`~ N ~ o
`"g~’~ ~8
`~._= ~ ~’a-.= or-= or-
`should be advised in regard to protection from cli-
`~- = o ~
`.~ ~ .-= ~ t,
`oa
`~ ~ ~
`> >. o
`....
`~.~ matic influences (both heat and cold), avoidance
`o > o_ ~
`of factors thattrigger or exacerbate flushing or that
`~ ~= ~
`¯ ~ ~ - ~
`8 ~g e ~ ~
`¯ - o ¯
`=~_ ~ .-n o o E o~ = ~._
`nn~8
`irritate the often-sensitive sldn, appropriate care of
`nb~° ~ .o_ ~ "~ ~ ~--o n~._~_o~nO " -o~ o= ~ ~o ~
`the facial skin (Table 2), and a strategy for mainte-
`~ o o o
`~-= ~ ~ ~° ~° >. ~ .~=n~o o -o o ~ ~
`...... s " o o ~ =- ....
`nance 0fremissi0n when the condition improves.
`o-o g ~g
`The choice of medications, dosages, and duration
`o ~ ~
`~ ~ ~
`of therapy is often based on clinical experience.
`~ n ~ ~_ Off-label prescription-drug use is common. ~
`~_~.E ~ o
`n°~=
`. ~ ~ ~ o
`~- ~ ~ ~ ~ o ,, ~
`a -~ :e ~ >
`Flushing, with persistent central facial erythema
`>.n ~ o:~ o~ .
`,~.~n ,1,
`(erythematotelangiectaticrosacea), is probably the
`~ ~ ~ ~ ~
`~’-.~c ~ ~ ,,,n
`~ ~ o-~ = o = ~
`o 7
`.-~_ v 8-~
`~ most common presentation ofrosacea.6 Although
`~z o.- t~ t~
`~ ~ .- ~
`o
`- o ~
`c E .-- ~_oo c~
`~ ~__. ga
`¯ -- 000a o -- oa oa
`it has been suggested that r0sacea is essentially a
`n~=.->" o = ~=~ ~-~,~>" o .= >,
`~,~ o o~
`o .~..~ ~’.~ ~ ~v~
`n~.- ~
`cutaneous vascular disorder, facial flushingis not
`
`~n= ~ ~ ~ ~~ ~ .... -~ ~ r_ ~= 8 o .-._° ~
`.... ~ o := o ~ =
`always a feature; patients who report flushing as
`~ n
`~o ._~ ~ ~ ~ ~ ~. = ~
`their only symptom should not receive a diagnosis
`~
`~ 0
`~._ ~ ~
`~_~ ~
`:~ ~ >-
`o o
`~ o o
`of"prerosacea," since, in many such patients, ro-
`0 oa~
`--
`.~.~ ~ ~,~
`sacea never develops. Common causes of flushing
`.... ¯ a- o ~ ~ o
`~ ~ ..... ~ =
`(e.g., psychosocial factors or anxiety, food, alcohol
`or drugs, or menopause) should become apparent
`n o= ~._= when a medical history is tal<en. Prolonged episodes
`o~: ~.~n
`of severe flushing accompanied by sweating, flush-
`~- z-~n ~ ~ = r~ ~
`o o o g o ~ ~
`ingthatisnotlimitedtotheface, and, especially, sys-
`~ ~ ~ ~ 8 ~
`temic symptoms such as diarrhea, wheezing, head-
`<..5 o.E o.~
`ache, palpitations, or weakness indicate the need
`
`~ >
`
`~ ~a= ~a
`
`c m ~-E ~
`
`SUBTYPE 1
`
`2O
`
`~ ~
`.-
`¢0n ~
`~.._~ ~ ~ .o
`~ n 8 ~,
`~ ~ ~ = =
`~ ~ ~ 8_~
`
`~ On -O O
`
`ca-
`
`~"
`~_.
`~ ~
`8
`0
`
`N ENGL J MED 352;8 WWW. NEJM.ORG FEBRUARY 24, 2005
`
`795
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ALLERGAN INC on September 24, 2018. For personal use only¯ No other uses without permission.
`Copyright © 2005 Massachusetts Medical Society¯ All rights reserved.
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`3 ofll
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`The NEW ENGLAND JOURNAL qfMEDICINE
`
`Table 2. General Nonpharmacologic Guidelines for the Management
`of Rosacea.
`
`Reassure patients about the benign nature of the disorder and the rarity of rhi-
`nophyma (particularly in women).
`Direct patients to Web sites such as those of the National Rosacea Society
`(www.rosacea.org) and the American Academy of Dermatology
`(www.aad.org), where patient-related information can be accessed,
`Advise patients to keep a daily diary to identify precipitating or exacerbating
`factors.
`Suggest a daily application of combined ultraviolet-A-protective and ultravio-
`let-B-protective sunscreen (with a sun-protection factor of 15 or greater),
`Sunscreen may be incorporated into moisturizer or topical medication,
`Vehicle formulations with dimethicone and cyclomethicone may be less
`irritating than others. Sun-blocking creams containing titanium dioxide
`and zinc oxide are usually well tolerated,
`Suggest a daily application of soap-free cleansers, silicone facial foundations,
`and liquid film-forming moisturizers.
`Suggest cosmetic coverage of excess redness with brush application; matte-
`finish, water-soluble facial powder containing inert green pigment helps
`neutralize erythema,
`Advise patients to avoid potentially exacerbating factors:
`Overly strenuous exercise, hot and humid atmosphere, emotional upset,
`alcohol, hot beverages, spicy foods, and large hot meals,
`Exposure to sun or to intense cold or harsh winds.
`Perfumed sunscreens or those containing insect repellents,
`Astringents and scented products containing hydroalcoholic extracts or
`sorbic acid.
`Cleansers containing acetone or alcohol,
`Abrasive or exfoliant preparations.
`Vigorous rubbing of the skin.
`Toners or moisturizers containing glycolic acid.
`If possible, medications that may exacerbate flushing (e.g., vasodilative
`drugs, nicotinic acid and amyl nitrite, calcium-channel-blocking
`agents, and opiates),
`
`, . ~
`
`,,
`
`~ ~’ " ’’~ "’
`’ - " ),~;’ ".x
`
`¯
`
`--.
`
`,
`’
`
`-
`
`-
`
`’
`
`" ; "~" ".’% t’ ,,’
`- ? ". :
`’
`i ,’
`¯
`, b i.
`; .... ~,
`- .... " -.~" "
`; :t-~ :
`i:: L~..:~x ’-.
`~M ,~,.j,, ,~
`~-.x.,
`~" ~ ’,’~,,.\i a, ~,"’
`
`
`-
`
`,
`
`,,
`
`~~L
`
`for investigations to rule out rare conditions that
`may be characterized by flushing (e.g., the carcinoid
`syndrome, pheochromocytoma, or mastocytosis).2~
`Telangiectatic vessels are usually prominent on
`the cheeks and nose in grades 2 and 3 of subtype 1
`rosacea (Fig. 1) and contribute to the facial erythe-
`ma, Erythematotelangiectatic rosacea is difficult to
`distinguish from the effects of chronic actinic dam-
`age, which may coexist. Since the management of
`the two conditions is similar, this distinction is not
`essential for patient care. Erythematotelangiectatic
`rosacea may occasionally mimic facial contact der-
`matitis, the "butterfly rash" of lupus erythematosus,
`or photosensitivity; if the diagnosis is uncertain,
`skin biopsies, serologic screening for antinuclear
`and anticytoplasmic autoantibodies, or other inves-
`tigations may be indicated.
`Subtype i rosacea is poorly responsive to treat-
`ment. The measures outlined in Table 2 are partic-
`ularly relevant for patients with subtype 1, who of-
`ten have sensitive, easilyirritated skin. There are few
`studies of the effectiveness of medical treatments
`for flushingin patients with rosacea. Beta-blockers
`in low doses (e.g., nadolol, 20 to 40 mg daily)= as
`well as clonidine and spironolactone have been used
`to treat flushing in patients with rosacea, but evi-
`dence from randomized trials is lacking to support
`the effectiveness of these agents. Endoscopic trans-
`thoracic sympathectomy has been used successfully
`to treat socially disabling blushing23; however, its
`use as a treatment for rosacea is not recommended,
`owing to rare but serious complications such as
`pneumothorax and pulmonary embolism, as well
`as postoperative increases in episodes of abnormal
`sweating.
`If the telangiectatic component is prominent, as
`it is in grade-2-to-3 disease, ablation of vessels by
`laser can be helpful. A nonblinded, uncontrolled
`study of 16 patients who had erythematotelangiec-
`tatic rosacea and were treated with pulsed-dye-
`laser therapy showed a significant improvement in
`erythema and quality of life after treatment. A1-
`though topical and systemic therapies, as outlined
`forpapulopustularrosaceabelow, are often used to
`treat patients with erythematotelangiectatic rosa-
`cea, there is little evidence of the efficacy of these
`agents. In addition, topical therapy may irritate the
`sensitive skin of patients with subtype i rosacea.
`
`24
`
`SUBTYPE 2
`Small, dome-shaped erythematous papules, some
`of which have tiny surmounting pustules, on the
`
`~
`
`Figure 1. Erythematotelangiectatic (Subtype 1) Rosacea.
`
`Prominent telangiectasias and erythema of the medial cheek are evident in
`this exam pie of grade 2 disease. As the erythema subsides, the telangiectasias
`often become more evident. This patient, who has fair skin and works out-
`side, reported sensitive, easily irritated skin and frequent flushing.
`
`i"
`
`796
`
`N ENGL J MED 352;8 WWW. NEJM.ORG FEBRUARY 24, 2005
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`

`CLINICAL PRACTICE
`
`convexities of the central portion of the face, with
`background erythema (Fig. 2), typify papulopustu-
`lar rosacea.6 In grade 3 disease, plaques can form
`from the coalescence of inflammatory lesions (Fig.
`3). Telangiectatic vessels, varying degrees of edema,
`ocular inflammation, and a tendency to flush are
`present in some patients. The differential diagnosis
`includes acne vulgaris, perioral dermatitis, and seb-
`orrheic dermatitis. Patients with acne vulgaris have
`less erythema, are often younger, and have oily skin
`with blackheads and whiteheads (comedones), larg-
`er pustules and nodulocystic lesions, and a tendency
`to scarring. In patients with perioral dermatitis, mi-
`cropustules and microvesicles around the mouth or
`eyes and dry, sensitive skin may follow the inappro-
`priate use of topical corticosteroids. Seborrheic der-
`matitis may accompany rosacea and contribute to
`the facial erythema, butitis distinguished from ro-
`sacea by a prominence of yellowish scaling around
`the eyebrows and alae nasi, together with trouble-
`some dandruff.
`
`Management
`Systemic or topical antibiotics, or both, are the
`mainstays of therapy for subtype 2 rosacea (Table 3),
`and the response is often satisfactory (Fig. 4A and
`4B). Moderate-to-severe (i.e., grade 2 or 3) papulo-
`pustular rosacea may require systemic therapy to
`achieve clearance of inflammatory skin lesions,
`whereas milder (grade 1 and some cases of grade 2)
`disease can often be treated with topical medica-
`tions alone.2s Although data are lacking to support
`the combined use of topical and systemic therapies,
`many clinicians recommend such a combination for
`the treatment of moderate-to-severe disease.2°,2s
`On the basis of an analysis that pooled data from
`two randomized trials, van Zuuren and colleagues
`concluded that there was strong evidence of the ef-
`ficacy of topical metronidazole and azelaic acid
`cream.26 Sixty-eight of 90 patients (76 percent)
`treated with topical metronidazole for eight or nine
`weeks considered their rosacea to be improved, as
`compared with 32 of 84 patients (38 percent) in the
`placebo group,26 Significant reductions in the num-
`ber of inflammatory lesions and in erythema were
`reported in two large placebo-controlled, double-
`blind studies of a 15 percent azelaic acid gel applied
`twice daily.27 A double-blind, randomized, parallel-
`group trial involving 251 patients with papulopus-
`tolar rosacea28 demonstrated the superiority 0f15
`percent azelaic acid gel over 0.75 percent metroni-
`dazole gel applied twice daily for 15 weeks. In a dou-
`
`--x ~-~,a._
`
`--
`
`.:
`
`~__~,~L’-~
`
`Figure 2. Papulopustular (Subtype 2) and Ocular (Subtype 4) Rosacea of Mod-
`erate Severity.
`In this example ofgrade-2-to-3 disease, the typical distribution of papules and
`)ustules on a background of inflammatory erythema is seen over the con-
`vexities of the central portion of the face, with sparing of the periocular area.
`Grade-l-to-2 ocular rosacea (erythema and edema of the upper eyelids)
`is also present.
`
`’~
`
`*-
`
`~,-,~,
`
`.
`
`Figure 3. Severe Papulopustular Rosacea with Moderate
`Ocular Involvement.
`
`In this patient with grade 3 papulopustular disease, in-
`flammatory lesions have coalesced into an erythema-
`tous plaque below the eye. Note the multiple small,
`studded pustules on the surface of the plaque and the
`inflammatory lesions on the lower eyelid (grade 2 ocular
`rosacea).
`
`N ENGLJ MED 352;8 WWW.N EJ M.ORG FEBRUARY 24, 2OO5
`
`797
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`The NEW ENGLAND JOURNAL 0fMEDICINE
`
`Table 3. Treatment of Papulopustular Rosacea.*
`
`Medication Properties and Actions
`
`Dosage and Duration"i"
`
`Co ntrai nd icatio n s
`and Side Effects’.;."
`
`Comments
`
`Topical
`Metronidazole(0.75%gel Antibacterial;antiinflam- Applied once or twicedai- Contraindications: women of Gel and cream and
`ly. Can be used as ini-
`childbearing age not on
`both concentra-
`or cream; 1% cream)
`matory,
`tial treatment to clear
`oral contraception should
`tions appear to be
`inflammatory lesions
`use with caution because
`equally effective.
`of possibility of-absorption
`or as indefinite main-
`tenance therapy after
`clearance with sys-
`
`and mutagenic effects.
`Side effects: gel preparation
`
`Azelaic acid
`(20% cream; 15% gel)
`
`Antibacterial; anti-
`inflammatory,
`
`temic therapy,
`
`Applied twice daily. Can
`be used as initial or
`indefinite mainte-
`nance therapy.
`
`may be irritating to skin.
`Transient watering of eyes
`
`may occu r when applied to
`periocular skin.
`
`Side effects: may cause mild
`burning or stinging sensa-
`tion when applied initially,
`Pruritus, dryness, or scal-
`ing can occun Rarely, con-
`tact dermatitis or facial
`edema may occun
`
`May be used in worn-
`en ofchildbearing
`age and during
`pregnancy.
`
`10% Sodium sulfaceta-
`mide and 5% sulfur in
`cream or lotion. Prep-
`arations may include
`10% urea; sunscreen;
`green tint.
`
`Antibacterial; keratolytic Applied twice daily. Can
`(sulfur); hydrating
`be used as initial or
`indefinite mainte-
`(urea).
`nance therapy.
`Cleanser preparation
`available.
`
`Contraindications: hypersensi- Sulfur component
`tivity to sulphonamide or
`may help accom-
`sulfun
`panying seborrhe-
`Side effects: rarely, systemic
`ic dermatitis. Sun-
`hypersensitivity reactions,
`screen or tinted
`May cause redness, peel-
`preparations may
`ing, and dryness of skin.
`reduce number of
`topical prepara-
`tions needed.
`
`Erythromycin
`
`(2% solution)
`
`Antibacterial; anti-
`inflammatory,
`
`Applied twice daily. Can
`be used as initial or
`indefinite mainte-
`nance therapy,
`
`Side effects: local irritation or May be used in preg-
`dryness,
`nancy. Alcohol in
`solution may re-
`duce tolerance.
`
`Tretinoin (0.025% cream Alters epidermal keratini- Applied at night. Can be Contraindications:teratogenic; Theoretically useful
`or lotion; 0.01% gel)
`zation. May improve
`used as initial or in-
`women ofchildbearing age
`for actinically
`definite maintenance
`photoaging changes,
`not on oral contraceptives
`damaged skin
`therapy,
`should use with caution.
`(common in
`Side effects: Irritating and
`rosacea).
`poorly tolerated by some
`patients. May cause photo-
`sensitivity. Use on dam-
`aged skin and contact with
`eyes should be avoided.
`
`Systemic
`Oxytetracycline Antibacterial; antiinflam- 250 to 500 mg twice daily Contraindications: should be
`
`matory, for 6 to 12 weeks to avoided bywomen who are
`achieve remission. In-
`pregnant, contemplating
`
`termittent low-dose
`therapy may prevent
`
`pregnancy, or lactating and
`by persons with impaired
`
`relapse,
`
`renal or hepatic function.
`Side effects: gastrointestinal
`
`upset; candida; photosen-
`sitivity; benign intracranial
`
`hypertension. May reduce
`effectiveness of oral contra-
`
`ceptives. May cause tooth
`discoloration or enamel hy-
`poplasia.
`Poor absorption if taken with
`
`food, milk, or some medi-
`cations.
`
`798
`
`N ENGL J MED 352;8 WWW. NEJM.ORG FEBRUARY 24, 2005
`
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`
`6 ofll
`
`

`

`CLINICAL PKACTICE
`
`Table 3. (Continued.)*
`
`Medication
`
`Properties and Actions
`
`Dosage and Durationi"
`
`Doxycycline
`
`Minocycline
`
`Antibacterial; antiinflam- 50 to 100 mg once or
`twice daily for 6 to 12
`rnatory,
`weeks.
`
`Contraindications
`and Side Effects.’.;."
`
`Same as for oxytetracycline.
`
`Comments
`
`May be taken with
`food.
`
`Antibacterial; antiinflam- 50 to 100 mg twice daily Contraindications: pregnancy Randomized, clinical
`or sustained-action
`or lactation. Persons with
`trials to support
`matory,
`formulation once dai-
`hepatic impairment should
`its use in rosacea
`ly for 6 to 12 weeks,
`use with caution,
`are lacking, but
`Side effects: gastrointestinal
`clinical impres-
`upset (but less than with
`sion is of-equal
`tetracycline); allergic reac-
`efficacy to oxytet-
`tions. Hyperpigmentation
`racycline. Unlike
`of-th e s kin m ay occu n
`oxytetracycli n e,
`Long-term use should be
`can be taken with
`avoided (hepatic damage
`food.
`or systemic-lu pus-erythe-
`matosus-like syndrome
`may be induced). Drug in-
`teractions with antacids,
`mineral supplements, anti-
`coagulants.
`
`Erythromycin
`
`Antibacterial; antiinflam- 250 to 500 mg once or
`twice daily for 6 to 12
`matory,
`weeks.
`
`Contraindications: severe
`hepatic impairment,
`Side effects: gastrointestinal
`upset; headache or rash.
`Drug interactions (many).
`
`Metronidazole
`
`Antibacterial; antiinflam- 200 mg once or twice dai- Contraindications: pregnant
`ly for 4 to 6 weeks,
`or lactating women should
`matory,
`use with caution,
`Side effects: gastrointestinal
`upset; leukopenia; neuro-
`logic effect (seizures or pe-
`ripheral neuropathy). Drug
`interactions with alcohol,
`anticoagulants, or pheno-
`barbital.
`
`Alternative to oxy-
`tetracycline or
`minocycline as
`first-line systemic
`treatment. Useful
`if-systemic thera-
`py necessary in
`
`oxytetracycline-
`intolerant or preg-
`nant or lactating
`patients.
`
`Side-effect profile lim-
`its its use to resis-
`tant cases for
`short periods.
`
`* Topical treatment alone is usually effective for mild-to-moderate (grade-l-to-2) papulopustular rosacea. Topical metronidazole, combination
`10 percent sodium sulf-acetamide and 5 percent sulfur, and 15 percent azelaic acid have been approved by the Food and Drug Administration
`for the treatment of- rosacea; however, several other topical medications are used off label. For patients with moderate-to-severe papulopus-
`tular rosacea (grade 2 to 3), oral medication is usually indicated. These patients may not tolerate topical medications initially, owing to in-
`flamed skin, but topical therapy may be added as the inflammation subsides and is used to maintain remission af-ter cessation of-oral therapy.
`
`"i" Dosage ranges relate to published reports and reflect the lack of- uniformity in the approach to the treatment of- papulopustular rosacea.
`:~" Contraindications and side effects are selected examples rather than a comprehensive summary.
`
`fur lotion with 0.75 percent metronidazole showed
`ble-blind study of 103 patients, a lotion containing
`10 percent sodium sulfacetamide and 5 percent sul- a significantly greater clearance of lesions among
`the patients treated with sodium sulfacetamide and
`fur reduced inflammatory lesions by 78 percent, as
`compared with a reduction of 36 percent in the pla-
`sulfur.3° An uncontrolled study showed a reduction
`cebo group.29 An investigator-blinded study involv-
`in erythema, papules, and pustules in 13 of 15 pa-
`ing 63 patients that compared the combination of tients (87 percent) who were treated with topical
`10 percent sodium sulfacetamide and 5 percent sul-
`erythromycin applied twice daily for four weeks.3z
`
`N ENGL J MED 352;8 WWW. NEJM.ORG FEBRUARY 24, 2005
`
`799
`
`The New England Joumal of Medicine
`Downloaded from nejm.org at ALLERGAN INC on September 24, 2018. For personal use only. No other uses without permission.
`Copyright © 2005 Massachusetts Medical Society. All rights reserved.
`
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`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`A
`
`’- -~-~-~T
`
`_
`.~- ~ ,~
`"
`’-
`
`,.
`
`,
`
`"~’
`
`i
`
`B
`
`~<,
`
`-
`
`Figure 4. Response to Treatment in a Patient with Papulopustular Rosacea.
`
`three times per week; moderate or marked improve-
`ment was observed in all patients after four weeks
`of therapy.3s
`Oral isotretinoin in low doses has been reported
`to be effective in the control of rosacea that was
`otherwise resistantto treatment, but the ocular and
`cutaneous drying effects of this agent are poorly
`tolerated, and its potential for serious adverse ef-
`fects (including teratogenic effects) contradicts its
`use in routine care. Topical tretinoin has been re-
`ported to be as effective as oral isotretinoin after 16
`weeks of treatment36 and may be helpful in the treat-
`ment of patients with papulopustular rosacea who
`also have oily skin.37
`Anecdotal reports have suggested that Cucumis
`sativus (cucumber), applied in a cooled yogurt paste,
`is helpful in reducing facial edema ofrosacea that
`is otherwise resistant to treatment38 and that facial
`massage involving rotatory movements of the fin-
`gers from the central to the peripheral face may im-
`prove papulopustular and edematous skin chang-
`es.39 However, data that support the effectiveness
`of either of these treatments are lacking.
`
`This patient with grade-2-to-3 papulopustular rosacea (Panel A) was given
`oral antibiotics for six weeks, followed by topical maintenance therapy, as
`well as continuous application ofa sunscreen with a sun-protection factor
`of 15 or greater. Eight weeks after the initiation of therapy (Panel B), the
`inflammatory papules and pustules had cleared, although some residual
`erythema persisted.
`
`Maintenance Therapy
`Because relapse occurs in about one quarter of pa-
`tients within weeks after the cessation of systemic
`therapy,4° topical therapy is usually used in an effort
`to maintain remission.4~ The required duration of
`Evidence of the efficacy of oral metronidazole
`and tetracycline was also reported by van Zuuren et maintenance therapy is unknown, but a period of
`al.a6 Of 73 patients who were treated with tetracy-
`six months is generally advised.4a After this time,
`cline forfourto sixweeks, 56 (77 percent) werecon- some patients report that they can keep their skin
`sidered to have improvement, as compared with 28
`free ofpapulopustular lesions with topical therapy
`of 79 (35 percent) in the placebo group,a6 Among 14 applied on alternate days or twice weekly, whereas
`patients treated with 200 mg ofmetronidazole twice others require repeated courses of systemic medi-
`daily for six weeks, 10 were considered to have im- cation.
`provement, as compared with 2 of 13 patients (15
`percent) who received placebo pills.32 A double- SUBTYPE 3
`blind trial that compared 200 mg ofmetronidazole Phymatous rosacea is uncommon. The most fre-
`twice daily with 250 mg of tetracycline twice daily quent phymatous manifestation is rhinophyma
`for 12 weeks among 40 patients showed that the
`(known familiarly as "whiskeynose" or "rum blos-
`two agents were equally effective.33 Although both som"). In its severe forms (grade 3), rhinophyma
`minocycline and erythromycin are frequently used
`is a disfiguring condition ofthe nose resulting from
`in the systemic treatment ofrosacea, there are few hyperplasia of both the sebaceous glands and the
`data available on the effectiveness of these agents, connective tissue (Fig. 5). Rhinophyma occurs
`On the basis of clinical experience, some investiga- much more often in men than in women (approxi-
`mrs have suggested thatintermittentlow-dose anti- mate ratio, 20:1),43 and a number ofclinicopatho-
`biotic treatment (250 mg oftetracycline on alternate
`logic variants have been described.44 Although rhi-
`days) may be as effective as multiple daily doses.34 nophymais often referred to as "end-stage rosacea,"
`An uncontrolled study of 10 patients with moder-
`it may occur in patients with few or no other features
`ate or severe rosacea that had responded poorly to ofrosacea. The diagnosis is usually made on a clin-
`treatment were prescribed 250 mg ofazithromycin
`ical basis, but a biopsy may be necessary to distin-
`
`8OO
`
`N ENGL J MED 352;8 WWW.NEJM.ORG FEBRUARY 24, 2005
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ALLERGAN INC on September 24, 2018. For personal use only. No other uses without permission.
`Copyright © 2005 Massachusetts Medical Society. All rights reserved.
`
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`

`CLINICAL PKACTICE
`
`lids with warm water twice daily), fucidic acid, and
`metronidazole gel applied to lid margins are treat-
`ments that are frequently used to treat mild ocular
`rosacea. Systemic antibiotics are often additionally
`required for grade-2-to-3 disease, although limited
`data are available to support these approaches. In a
`double-blind, placebo-controlled trial, 35 patients
`with ocular rosacea who received 250 mg ofoxytet-
`racycline twice daily for six weeks had a significant-
`ly higher rate of remission than did patients who
`received a placebo (65 percentvs. 28 percent).49 In
`an uncontrolled study of 39 patients with cutane-
`ous rosacea (28 with ocular symptoms), 100 mg of
`doxycycline daily for 12 weeks improved symp-
`toms ofdryness, itching, blurred vision, and photo-
`sensitivity,s° After ocular symptoms subside, the
`maintenance of lid hygene and the use of artificial
`tears are usually recommended. However, such
`treatmentmaybeinadequate formoderate-to-severe
`ocular rosacea, and patients with persistent or po-
`tentially serious ocular symptoms should be re-
`ferred to an ophthalmologist.
`
`Figure 5. Advanced Rhinophyma (Subtype 3).
`
`In grade 3 rhinophyma, enlargement and distortion of
`the nose occur, with prominent pores and thickened skin
`due to hyperplasia of the sebaceous glands and fibrosis
`of the connective tissue. There is follicular prominence
`and a distorted nodular appearance. In this patient, the
`rhinophyma was accompanied by mild papulopustular
`rosacea, which responded well to topical medications.
`
`AREAS OF U NC E RTAI NTY
`
`guish atypical, or nodular, rhinophyma from lupus
`pernio (sarcoidosis of the nose); basal-cell, squa-
`mous-cell, and sebaceous carcinomas; angiosarco-
`The causes and pathogenesis of rosacea remain
`ma; and even nasal lymphoma.4s
`Data from randomized trials of therapies for rhi- poorly understood.4,sz Data from randomized, clin-
`ical trials on the efficacy and optimal duration of
`nophy