new england jurnal rosasea

n engl j med

352;8

www.nejm.org february

24, 2005

The

new england journal

of

medicine

793

clinical practice

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 formal guidelines,

when they exist. The article ends with the authors clinical recommendations.

Rosacea

Frank C. Powell, F.R.C.P.I.

From the Regional Centre of Dermatology,Mater Misericordiae Hospital, Dublin. Sendreprint requests to Dr. Powell at the Region-al Centre of Dermatology, Mater Misericor-diae Hospital, Eccles St., Dublin 7, Ireland,or at [email protected].

N Engl J Med 2005;352:793-803.

Copyright 2005 Massachusetts Medical Society.

A 47-year-old white woman reports facial redness and flushing. Her eyes are itchy andirritated. She thinks she may have rosacea and is worried that she will have a whiskeynose. On examination, multiple erythematous papules, pustules, and telangiectasiasare observed on a background of erythema of the central portion of her face. Howshould her case be managed?

A constellation of clinical symptoms and signs are included under the broad rubric ofrosacea. These consist of facial flushing, the appearance of telangiectatic vessels andpersistent redness of the face, eruption of inflammatory papules and pustules on thecentral facial convexities, and hypertrophy of the sebaceous glands of the nose, with fi-brosis (rhinophyma).

1

Ocular changes are present in more than 50 percent of patientsand range from mild dryness and irritation with blepharitis and conjunctivitis (commonsymptoms) to sight-threatening keratitis (rare).

2

Patients with rosacea may report in-creased sensitivity of the facial skin

3

and may have dry, flaking facial dermatitis, edemaof 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 ofrosacea 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 eachsubtype graded as 1 (mild), 2 (moderate), or 3 (severe).

7

The psychological, social, andoccupational effects of the disease on the patient should also be assessed and factoredinto treatment decisions.

The onset of rosacea usually occurs between the ages of 30 and 50 years.

8

Thecourse of the disease is typically chronic, with remissions and relapses. Some patientsidentify exacerbating factors, particularly in regard to flushing, such as heat, alcohol,sunlight, hot beverages, stress, menstruation, certain medications, and certain foods.

9

Rosacea is more common in women than in men, but men with rosacea are more proneto the development of thickening and distorting phymatous skin changes. Rosacea hasbeen anecdotally reported to be associated with seborrheic dermatitis (this associationis likely), with migraine headaches in women

10

(possible), and with

Helicobacter pylori

in-fection

11

(controversial). A rosacea-like eruption can be induced by the topical applica-tion of fluorinated corticosteroids

12

and tacrolimus ointment

13

to the face. In two Eu-ropean population studies, the prevalence of rosacea was reported to be 1.5 percent

14

and 10 percent,

15

but estimates are complicated by the difficulty of distinguishing be-tween chronic actinic damage and erythematotelangiectatic rosacea. Although rosaceacan occur in all racial and ethnic groups, white persons of Celtic origin are thought to beparticularly prone to the disorder,

16

and it is uncommon in persons with dark skin. Up to30 percent of patients report a family history of rosacea.

17

The common misconception

the clinical problem

The New England Journal of Medicine Downloaded from nejm.org on September 20, 2015. For personal use only. No other uses without permission.

Copyright 2005 Massachusetts Medical Society. All rights reserved.

n engl j med

352;8


24

,

2005

The

new england journal

of

medicine

794

Tabl

e 1.

Cla

ssifi

catio

n, F

eatu

res,

and

Tre

atm

ent o

f Ros

acea

.*

Subt

ype

Clin

ical

Fea

ture

sSe

veri

ty

Ther

apeu

tic A

ppro

ach

Com

men

ts

Gra

deFe

atur

es

Eryt

hem

atot

el-

angi

ecta

tic

(sub

type

1)

Pers

iste

nt e

ryth

ema

of th

e ce

ntra

l fac

e.

Flus

hing

; tel

angi

ecta

sias

oft

en p

rese

nt;

easi

ly ir

rita

ted

faci

al s

kin.

Pat

ient

may

re

port

stin

ging

or

burn

ing

of th

e fa

ce

and

have

sym

ptom

s of

ocu

lar r

osac

ea.

Rhi

noph

yma

occa

sion

ally

coe

xist

s.

1 2 3

Occ

asio

nal m

ild fl

ushi

ng; f

aint

per

sist

ent

eryt

hem

a; o

ccas

iona

l tel

angi

ecta

sias

.Fr

eque

nt tr

oubl

esom

e flu

shin

g; m

oder

ate

pers

iste

nt e

ryth

ema;

sev

eral

dis

tinct

tel-

angi

ecta

sias

.Fr

eque

nt s

ever

e flu

shin

g; p

rono

unce

d pe

rsis

-te

nt e

ryth

ema;

pos

sibl

e ed

ema;

man

y pr

omin

ent t

elan

giec

tasi

as.

Red

uce

flush

ing

and

redn

ess

and

min

i-m

ize

skin

irri

tatio

n. T

opic

al m

edi-

catio

ns r

ecom

men

ded

for

papu

lo-

pust

ular

ros

acea

are

not

indi

cate

d an

d m

ay c

ause

irri

tatio

n. S

yste

mic

tr

eatm

ents

use

d fo

r pa

pulo

pust

u-la

r ro

sace

a m

ay r

educ

e er

ythe

ma

if si

gnifi

cant

infla

mm

atio

n is

pre

sent

. A

blat

ive

ther

apy

of p

rom

inen

t ves

-se

ls fo

r gr

ade-

2-to

-3 d

isea

se.

Diff

icul

t to

trea

t sat

is-

fact

orily

.

Papu

lopu

stul

ar(s

ubty

pe 2

)Pe

rsis

tent

ery

them

a of

the

cent

ral f

ace;

do

me-

shap

ed e

ryth

emat

ous

papu

les;

sm

all p

ustu

les

surm

ount

som

e pa

p-ul

es. F

lush

ing,

tela

ngie

ctas

ias,

ocu

lar

infla

mm

atio

n, a

nd p

hym

atou

s sk

in

chan

ges

may

be

pres

ent.

1 2 3

Few

pap

ules

or

pust

ules

; mild

per

sist

ent

eryt

hem

a; n

o pl

aque

s.Se

vera

l pap

ules

or

pust

ules

; mod

erat

e pe

rsis

-te

nt e

ryth

ema;

no

plaq

ues.

Man

y or

ext

ensi

ve p

apul

es o

r pu

stul

es; p

ro-

noun

ced

pers

iste

nt e

ryth

ema;

infla

mm

a-to

ry p

laqu

es o

r ed

ema

may

be

pres

ent.

Topi

cal o

r sy

stem

ic m

edic

atio

ns fo

r gr

ade-

1-to

-2 d

isea

se; s

yste

mic

m

edic

atio

ns fo

r gr

ade

3.

Res

pons

e to

trea

tmen

t is

usu

ally

goo

d.

Mai

nten

ance

ther

-ap

y is

usu

ally

re-

quir

ed to

mai

ntai

n re

mis

sion

.

Phym

atou

s(s

ubty

pe 3

)Th

icke

ned

skin

with

pro

min

ent p

ores

. May

af

fect

nos

e (r

hino

phym

a

mos

t com

-m

on ty

pe),

chi

n (g

nath

ophy

ma)

, for

e-he

ad (

met

ophy

ma)

, ear

s (o

toph

yma)

, an

d ey

elid

s (b

leph

arop

hym

a). M

ay

occu

r in

isol

atio

n or

with

oth

er s

kin

chan

ges

of r

osac

ea (

flush

ing,

ery

the-

ma,

ede

ma,

tela

ngie

ctas

ias,

pap

ules

, pu

stul

es in

a n

asal

or

cent

ral-f

acia

l di

stri

butio

n) o

r w

ith o

cula

r ro

sace

a.

1 2 3

For

rhin

ophy

ma:

slig

ht p

uffin

ess

of n

ose;

slig

ht p

rom

inen

ce o

f fol

licul

ar o

rific

es

(pat

ulou

s fo

llicl

es);

no

clin

ical

ly a

ppar

ent

hype

rtro

phy

of c

onne

ctiv

e tis

sue

or s

eba-

ceou

s gl

ands

; no

chan

ge in

nas

al c

onto

ur.

For

rhin

ophy

ma:

bul

bous

nas

al s

wel

ling;

m

oder

atel

y di

late

d pa

tulo

us fo

llicl

es; c

lini-

cally

app

aren

t mild

hyp

ertr

ophy

of t

he s

e-ba

ceou

s gl

ands

or c

onne

ctiv

e tis

sue,

with

ch

ange

in n

asal

con

tour

but

with

out n

od-

ular

com

pone

nt.

For r

hino

phym

a: m

arke

d na

sal s

wel

ling;

larg

e di

late

d fo

llicl

es; d

isto

rtio

n of

nas

al c

on-

tour

due

to h

yper

trop

hy o

f the

seb

aceo

us

glan

ds o

r co

nnec

tive

tissu

e, w

ith n

odul

ar

com

pone

nt.

Rhi

noph

yma

(gra

des

2 an

d 3)

may

re-

spon

d w

ell t

o su

rgic

al o

r la

ser

ther

-ap

y. O

ther

phy

mat

ous

skin

cha

nges

ar

e ve

ry d

iffic

ult t

o tr

eat b

ut m

ay

impr

ove

with

trea

tmen

t of i

nfla

m-

mat

ory

skin

lesi

ons,

if p

rese

nt.

All

phym

atou

s sk

in

chan

ges

are

rare

. Th

e m

ost c

omm

on

form

(rh

inop

hym

a)

occu

rs p

redo

mi-

nant

ly in

men

.



n engl j med

352;8


24, 2005

clinical practice

795

that both the facial redness and the rhinophyma as-sociated with rosacea are due to excessive alcoholconsumption makes rosacea a socially stigmatizingcondition for many patients.

The diagnosis of rosacea is a clinical one. There isno confirmatory laboratory test. Biopsy is warrantedonly to rule out alternative diagnoses, since histo-pathological findings are not diagnostic.

18

The differential diagnosis and therapy vary ac-cording to subtype (Table 1). Rosacea that is mani-fested predominantly by flushing is difficult to treat,but the condition may improve with the manage-ment of other manifestations and the avoidanceof provoking or triggering factors. Inflammatorychanges in the skin are usually responsive to medi-cal therapies and heal without scarring, whereas tel-angiectasias and phymatous changes often requirelaser or surgical intervention. Ocular rosacea is usu-ally mild and responsive to lid hygiene, tear replace-ment, and topical or systemic antibiotics, but pa-tients with persistent or severe ocular disease shouldbe referred to an ophthalmologist. All patientsshould be advised in regard to protection from cli-matic influences (both heat and cold), avoidanceof factors that trigger or exacerbate flushing or thatirritate the often-sensitive skin, appropriate care ofthe facial skin (Table 2), and a strategy for mainte-nance of remission when the condition improves.The choice of medications, dosages, and durationof therapy is often based on clinical experience.Off-label prescription-drug use is common.

19

subtype 1

Flushing, with persistent central facial erythema(erythematotelangiectatic rosacea), is probably themost common presentation of rosacea.

6

Althoughit has been suggested that rosacea is essentially acutaneous vascular disorder,

20

facial flushing is notalways a feature; patients who report flushing astheir only symptom should not receive a diagnosisof prerosacea, since, in many such patients, ro-sacea never develops. Common causes of flushing(e.g., psychosocial factors or anxiety, food, alcoholor drugs, or menopause) should become apparentwhen a medical history is taken. Prolonged episodesof severe flushing accompanied by sweating, flush-ing that is not limited to the face, and, especially, sys-temic symptoms such as diarrhea, wheezing, head-ache, palpitations, or weakness indicate the need

strategies and evidence

*A

dapt

ed fr

om W

ilkin

et a

l.

6,7

In

gen

eral

, 1 d

enot

es m

ild d

isea

se, 2

mod

erat

e di

seas

e, a

nd 3

sev

ere

dise

ase,

but

gra

des

of s

ever

ity a

re n

ot a

lway

s cl

earl

y de

fined

. Pat

ient

s m

ay h

ave

mor

e th

an o

ne s

ubty

pe, a

nd th

e gr

ade

of s

ever

ity s

houl

d be

ass

esse

d in

eac

h of

thes

e. P

atie

nts

shou

ld a

lso

be a

sked

to g

rade

the

psyc

holo

gica

l, so

cial

, and

occ

upat

iona

l effe

cts

of th

eir d

isea

se o

n a

sim

ilar s

cale

. For

exa

mpl

e,

in g

rade

1 (

mild

), th

e pa

tient

is c

onsc

ious

of t

he c

ondi

tion,

but

it d

oes

not c

ause

em

barr

assm

ent o

r inh

ibit

soci

al fu

nctio

ning

; in

grad

e 2

(mod

erat

e), t

he p

atie

nt is

con

stan

tly a

war

e of

the

rosa

cea

duri

ng s

ocia

l situ

atio

ns a

nd it

regu

larl

y ca

uses

em

barr

assm

ent;

in g

rade

3 (

seve

re),

the

patie

nt is

con

stan

tly th

inki

ng a

bout

the

cond

ition

and

avo

ids

soci

al in

tera

ctio

n be

caus

e of

it. S

uch

grad

ing

on th

e pa

rt o

f the

pat

ient

faci

litat

es e

valu

atio

n of

the

over

all e

ffect

of t

he d

isea

se o

n hi

m o

r he

r an

d gu

ides

ass

essm

ent o

f the

effi

cacy

of t

hera

py.

Ocu

lar

(sub

type

4)

Sens

atio

n of

fore

ign

body

in th

e ey

e; te

l-an

giec

tasi

a an

d er

ythe

ma

of li

d m

ar-

gins

, oft

en w

ith s

calin

g. C

onju

nctiv

al

inje

ctio

n; r

ecur

rent

cha

lazi

on o

r ho

rdeo

lum

. Ker

atiti

s, e

pisc

leri

tis o

r sc

leri

tis, a

nd ir

itis

may

occ

ur, t

houg

h ra

rely

. May

pre

cede

, fol

low

, or

occu

r si

-m

ulta

neou

sly

with

cut

aneo

us c

hang

es.

Bot

h ey

es a

re u

sual

ly a

ffect

ed.

1 2 3

Mild

itch

, dry

ness

, or

gritt

ines

s of

eye

s; fi

ne

scal

ing

of li

d m

argi

ns; t

elan

giec

tasi

a an

d er

ythe

ma

of li

d m

argi

ns; m

ild c

onju

nctiv

al

inje

ctio

n (m

ild c

onge

stio

n of

con

junc

tival

ve

ssel

s).

Bur

ning

or s

tingi

ng o

f eye

s; c

rust

ing

or ir

regu

-la

rity

of l

id m

argi

ns, w

ith e

ryth

ema

and

edem

a; d

efin

ite c

onju

nctiv

al h

yper

emia

or

inje

ctio

n; fo

rmat

ion

of c

hala

zion

or

hord

eolu

m.

Pain

, pho

tose

nsiti

vity

, or

blur

red

visi

on; s

e-ve

re li

d ch

ange

s, w

ith lo

ss o

f las

hes;

se-

vere

con

junc

tival

infla

mm

atio

n; c

orne

al

chan

ges,

with

pot

entia

l los

s of

vis

ion;

ep

iscl

eriti

s or

scl

eriti

s; ir

itis.

Topi

cal m

edic

atio

n fo

r gra

de 1

; sys

tem

-ic

med

icat

ion

for

grad

e 2.

Ref

er

patie

nts

with

per

sist

ent g

rade

1

or 2

dis

ease

or

susp

ecte

d gr

ade

3 di

seas

e to

oph

thal

mol

ogis

t.

May

occ

ur in

the

maj

or-

ity o

f ros

acea

cas

es,

but o

ften

not

di-

agno

sed.

Vis

ion-

thre

aten

ing

ocul

ar

infla

mm

atio

n is

ra

re.



n engl j med

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The

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796

for investigations to rule out rare conditions thatmay be characterized by flushing (e.g., the carcinoidsyndrome, pheochromocytoma, or mastocytosis).

21

Telangiectatic vessels are usually prominent onthe cheeks and nose in grades 2 and 3 of subtype 1rosacea (Fig. 1) and contribute to the facial erythe-ma. Erythematotelangiectatic rosacea is difficult todistinguish from the effects of chronic actinic dam-age, which may coexist. Since the management ofthe two conditions is similar, this distinction is notessential for patient care. Erythematotelangiectaticrosacea 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 antinuclearand anticytoplasmic autoantibodies, or other inves-tigations may be indicated.

Subtype 1 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, easily irritated skin. There are fewstudies of the effectiveness of medical treatmentsfor flushing in patients with rosacea. Beta-blockersin low doses (e.g., nadolol, 20 to 40 mg daily)

22

aswell as clonidine and spironolactone have been usedto treat flushing in patients with rosacea, but evi-dence from randomized trials is lacking to supportthe effectiveness of these agents. Endoscopic trans-thoracic sympathectomy has been used successfullyto treat socially disabling blushing

23

; however, itsuse as a treatment for rosacea is not recommended,owing to rare but serious complications such aspneumothorax and pulmonary embolism, as wellas postoperative increases in episodes of abnormalsweating.

If the telangiectatic component is prominent, asit is in grade-2-to-3 disease, ablation of vessels bylaser can be helpful. A nonblinded, uncontrolledstudy of 16 patients who had erythematotelangiec-tatic rosacea and were treated with pulsed-dyelaser therapy showed a significant improvement inerythema and quality of life after treatment.

24

Al-though topical and systemic therapies, as outlinedfor papulopustular rosacea below, are often used totreat patients with erythematotelangiectatic rosa-cea, there is little evidence of the efficacy of theseagents. In addition, topical therapy may irritate thesensitive skin of patients with subtype 1 rosacea.

subtype 2

Small, dome-shaped erythematous papules, someof which have tiny surmounting pustules, on the

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-Aprotective and ultravio-let-Bprotective 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-channelblocking agents, and opiates).

Figure 1. Erythematotelangiectatic (Subtype 1) Rosacea.

Prominent telangiectasias and erythema of the medial cheek are evident in this example 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.



n engl j med

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797

convexities of the central portion of the face, withbackground erythema (Fig. 2), typify papulopustu-lar rosacea.

6

In grade 3 disease, plaques can formfrom the coalescence of inflammatory lesions (Fig.3). Telangiectatic vessels, varying degrees of edema,ocular inflammation, and a tendency to flush arepresent in some patients. The differential diagnosisincludes acne vulgaris, perioral dermatitis, and seb-orrheic dermatitis. Patients with acne vulgaris haveless erythema, are often younger, and have oily skinwith blackheads and whiteheads (comedones), larg-er pustules and nodulocystic lesions, and a tendencyto scarring. In patients with perioral dermatitis, mi-cropustules and microvesicles around the mouth oreyes and dry, sensitive skin may follow the inappro-priate use of topical corticosteroids. Seborrheic der-matitis may accompany rosacea and contribute tothe facial erythema, but it is distinguished from ro-sacea by a prominence of yellowish scaling aroundthe eyebrows and alae nasi, together with trouble-some dandruff.

Management

Systemic or topical antibiotics, or both, are themainstays of therapy for subtype 2 rosacea (Table 3),and the response is often satisfactory (Fig. 4A and4B). Moderate-to-severe (i.e., grade 2 or 3) papulo-pustular rosacea may require systemic therapy toachieve 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.

25

Although data are lacking to supportthe combined use of topical and systemic therapies,many clinicians recommend such a combination forthe treatment of moderate-to-severe disease.

20,25

On the basis of an analysis that pooled data fromtwo randomized trials, van Zuuren and colleaguesconcluded that there was strong evidence of the ef-ficacy of topical metronidazole and azelaic acidcream.

26

Sixty-eight of 90 patients (76 percent)treated with topical metronidazole for eight or nineweeks considered their rosacea to be improved, ascompared with 32 of 84 patients (38 percent) in theplacebo group.

26

Significant reductions in the num-ber of inflammatory lesions and in erythema werereported in two large placebo-controlled, double-blind studies of a 15 percent azelaic acid gel appliedtwice daily.

27

A double-blind, randomized, parallel-group trial involving 251 patients with papulopus-tular rosacea

28

demonstrated the superiority of 15percent azelaic acid gel over 0.75 percent metroni-dazole gel applied twice daily for 15 weeks. In a dou-

Figure 2. Papulopustular (Subtype 2) and Ocular (Subtype 4) Rosacea of Mod-erate Severity.

In this example of grade-2-to-3 disease, the typical distribution of papules and pustules 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-1-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).



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Table 3. Treatment of Papulopustular Rosacea.*

Medication Properties and Actions Dosage and DurationContraindicationsand Side Effects Comments

TopicalMetronidazole (0.75% gel

or cream; 1% cream)Antibacterial; antiinflam-

matory.Applied once or twice dai-

ly. Can be used as ini-tial treatment to clear inflammatory lesions or as indefinite main-tenance therapy after clearance with sys-temic therapy.

Contraindications: women of childbearing age not on oral contraception should use with caution because of possibility of absorption and mutagenic effects.

Side effects: gel preparation may be irritating to skin. Transient watering of eyes may occur when applied to periocular skin.

Gel and cream and both concentra-tions appear to be equally effective.

Azelaic acid(20% cream; 15% gel)

Antibacterial; anti-inflammatory.

Applied twice daily. Can be used as initial or indefinite mainte-nance therapy.

Side effects: may cause mild burning or stinging sensa-tion when applied initially. Pruritus, dryness, or scal-ing can occur. Rarely, con-tact dermatitis or facial edema may occur.

May be used in wom-en of childbearing 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 (sulfur); hydrating (urea).

Applied twice daily. Can be used as initial or indefinite mainte-nance therapy. Cleanser preparation available.

Contraindications: hypersensi-tivity to sulphonamide or sulfur.

Side effects: rarely, systemic hypersensitivity reactions. May cause redness, peel-ing, and dryness of skin.

Sulfur component may help accom-panying seborrhe-ic dermatitis. Sun-screen or tinted preparations may 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 dryness.

May be used in preg-nancy. Alcohol in solution may re-duce tolerance.

Tretinoin (0.025% cream or lotion; 0.01% gel)

Alters epidermal keratini-zation. May improve photoaging changes.

Applied at night. Can be used as initial or in-definite maintenance therapy.

Contraindications: teratogenic; women of childbearing age not on oral contraceptives should use with caution.

Side effects: Irritating and poorly tolerated by some patients. May cause photo-sensitivity. Use on dam-aged skin and contact with eyes should be avoided.

Theoretically useful for actinically damaged skin (common in rosacea).

SystemicOxytetracycline Antibacterial; antiinflam-

matory.250 to 500 mg twice daily

for 6 to 12 weeks to achieve remission. In-termittent low-dose therapy may prevent relapse.

Contraindications: should be avoided by women who are pregnant, contemplating pregnancy, or lactating and by persons with impaired 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.



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ble-blind study of 103 patients, a lotion containing10 percent sodium sulfacetamide and 5 percent sul-fur reduced inflammatory lesions by 78 percent, ascompared with a reduction of 36 percent in the pla-cebo group.

29

An investigator-blinded study involv-ing 63 patients that compared the combination of10 percent sodium sulfacetamide and 5 percent sul-

fur lotion with 0.75 percent metronidazole showeda significantly greater clearance of lesions amongthe patients treated with sodium sulfacetamide andsulfur.

30

An uncontrolled study showed a reductionin erythema, papules, and pustules in 13 of 15 pa-tients (87 percent) who were treated with topicalerythromycin applied twice daily for four weeks.

31

* Topical treatment alone is usually effective for mild-to-moderate (grade-1-to-2) papulopustular rosacea. Topical metronidazole, combination 10 percent sodium sulfacetamide 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 after cessation of oral therapy.

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.

Table 3. (Continued.)*

Medication Properties and Actions Dosage and DurationContraindicationsand Side Effects Comments

Doxycycline Antibacterial; antiinflam-matory.

50 to 100 mg once or twice daily for 6 to 12 weeks.

Same as for oxytetracycline. May be taken with food.

Minocycline Antibacterial; antiinflam-matory.

50 to 100 mg twice daily or sustained-action formulation once dai-ly for 6 to 12 weeks.

Contraindications: pregnancy or lactation. Persons with hepatic impairment should use with caution.

Side effects: gastrointestinal upset (but less than with tetracycline); allergic reac-tions. Hyperpigmentation of the skin may occur. Long-term use should be avoided (hepatic damage or systemic-lupus-erythe-matosuslike syndrome may be induced). Drug in-teractions with antacids, mineral supplements, anti-coagulants.

Randomized, clinical trials to support its use in rosacea are lacking, but clinical impres-sion is of equal efficacy to oxytet-racycline. Unlike oxytetracycline, can be taken with food.

Erythromycin Antibacterial; antiinflam-matory.

250 to 500 mg once or twice daily for 6 to 12 weeks.

Contraindications: severe hepatic impairment.

Side effects: gastrointestinal upset; headache or rash. Drug interactions (many).

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.

Metronidazole Antibacterial; antiinflam-matory.

200 mg once or twice dai-ly for 4 to 6 weeks.

Contraindications: pregnant or lactating women should use with caution.

Side effects: gastrointestinal upset; leukopenia; neuro-logic effect (seizures or pe-ripheral neuropathy). Drug interactions with alcohol, anticoagulants, or pheno-barbital.

Side-effect profile lim-its its use to resis-tant cases for short periods.



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Evidence of the efficacy of oral metronidazoleand tetracycline was also reported by van Zuuren etal.

26

Of 73 patients who were treated with tetracy-cline for four to six weeks, 56 (77 percent) were con-sidered to have improvement, as compared with 28of 79 (35 percent) in the placebo group.

26

Among 14patients treated with 200 mg of metronidazole twicedaily for six weeks, 10 were considered to have im-provement, as compared with 2 of 13 patients (15percent) who received placebo pills.

32

A double-blind trial that compared 200 mg of metronidazoletwice daily with 250 mg of tetracycline twice dailyfor 12 weeks among 40 patients showed that thetwo agents were equally effective.

33

Although bothminocycline and erythromycin are frequently usedin the systemic treatment of rosacea, there are fewdata available on the effectiveness of these agents.On the basis of clinical experience, some investiga-tors have suggested that intermittent low-dose anti-biotic treatment (250 mg of tetracycline on alternatedays) may be as effective as multiple daily doses.

34

An uncontrolled study of 10 patients with moder-ate or severe rosacea that had responded poorly totreatment were prescribed 250 mg of azithromycin

three times per week; moderate or marked improve-ment was observed in all patients after four weeksof therapy.

35

Oral isotretinoin in low doses has been reportedto be effective in the control of rosacea that wasotherwise resistant to treatment, but the ocular andcutaneous drying effects of this agent are poorlytolerated, and its potential for serious adverse ef-fects (including teratogenic effects) contradicts itsuse in routine care. Topical tretinoin has been re-ported to be as effective as oral isotretinoin after 16weeks of treatment

36

and may be helpful in the treat-ment of patients with papulopustular rosacea whoalso have oily skin.

37

Anecdotal reports have suggested that

Cucumissativus

(cucumber), applied in a cooled yogurt paste,is helpful in reducing facial edema of rosacea thatis otherwise resistant to treatment

38

and that facialmassage 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 effectivenessof either of these treatments are lacking.

Maintenance Therapy

Because relapse occurs in about one quarter of pa-tients within weeks after the cessation of systemictherapy,

40

topical therapy is usually used in an effortto maintain remission.

41

The required duration ofmaintenance therapy is unknown, but a period ofsix months is generally advised.

42

After this time,some patients report that they can keep their skinfree of papulopustular lesions with topical therapyapplied on alternate days or twice weekly, whereasothers require repeated courses of systemic medi-cation.

subtype 3

Phymatous rosacea is uncommon. The most fre-quent phymatous manifestation is rhinophyma(known familiarly as whiskey nose or rum blos-som). In its severe forms (grade 3), rhinophymais a disfiguring condition of the nose resulting fromhyperplasia of both the sebaceous glands and theconnective tissue (Fig. 5). Rhinophyma occursmuch more often in men than in women (approxi-mate ratio, 20:1),

43

and a number of clinicopatho-logic variants have been described.

44

Although rhi-nophyma is often referred to as end-stage rosacea,it may occur in patients with few or no other featuresof rosacea. The diagnosis is usually made on a clin-ical basis, but a biopsy may be necessary to distin-

Figure 4. Response to Treatment in a Patient with Papulopustular Rosacea.

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 of a 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.

A

B



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guish atypical, or nodular, rhinophyma from lupuspernio (sarcoidosis of the nose); basal-cell, squa-mous-cell, and sebaceous carcinomas; angiosarco-ma; and even nasal lymphoma.

45

Data from randomized trials of therapies for rhi-nophyma and long-term follow-up studies of recur-rence rates are lacking. Clinical experience suggeststhat grades 2 and 3 rhinophyma respond well, atleast initially, to surgical excision, electrosurgery, orcarbon dioxidelaser therapy. A case series of 30 pa-tients who were treated with carbon dioxide lasersand followed for one to three years showed goodcosmetic results in almost all the patients.

46

subtype 4

Ocular rosacea is common but often not recog-nized by the clinician.

47

It may precede, follow, oroccur simultaneously with the skin changes typicalof rosacea. In the absence of accompanying skinchanges, ocular rosacea can be difficult to diagnose,and there is no test that will confirm the diagnosis.Patients usually have mild, nonspecific symptoms,such as burning or stinging of the eyes. A sensationof dryness is common, and tear secretion is fre-quently decreased.

48

Mild-to-moderate ocular rosa-cea (including blepharoconjunctivitis, chalazia, andhordeola) occurs frequently, whereas serious (grade3) disease with the potential for visual loss, such asthat which results from keratitis, occurs rarely.

Artificial tears, eyelid hygiene (i.e., cleaning the

lids with warm water twice daily), fucidic acid, andmetronidazole gel applied to lid margins are treat-ments that are frequently used to treat mild ocularrosacea. Systemic antibiotics are often additionallyrequired for grade-2-to-3 disease, although limiteddata are available to support these approaches. In adouble-blind, placebo-controlled trial, 35 patientswith ocular rosacea who received 250 mg of oxytet-racycline twice daily for six weeks had a significant-ly higher rate of remission than did patients whoreceived a placebo (65 percent vs. 28 percent).

49

Inan uncontrolled study of 39 patients with cutane-ous rosacea (28 with ocular symptoms), 100 mg ofdoxycycline daily for 12 weeks improved symp-toms of dryness, itching, blurred vision, and photo-sensitivity.

50

After ocular symptoms subside, themaintenance of lid hygene and the use of artificialtears are usually recommended. However, suchtreatment may be inadequate for moderate-to-severeocular rosacea, and patients with persistent or po-tentially serious ocular symptoms should be re-ferred to an ophthalmologist.

The causes and pathogenesis of rosacea remainpoorly understood.

4,51

Data from randomized, clin-ical trials on the efficacy and optimal duration ofmany of the therapies, including complementarytherapies that are frequently used by patients,

52

arelacking. The possibility of emergence and carriageon the skin of resistant organisms is a concern withregard to the prolonged use of topical and systemicantibiotics.

There are no specific guidelines for the manage-ment of rosacea.

Rosacea is a diagnostic term applied to a spec-trum of changes in the skin and eyes. Until the caus-es and pathogenesis are better understood, the clas-sification of rosacea by its predominant features andgrading according to severity (Table 1) are recom-mended to guide management. The emotional ef-fect of rosacea on the patient must also be consid-ered in the management of this condition, andadvice on improving the cosmetic appearance of theskin is an important aspect of overall care.

areas of uncertainty

guidelines

summary of recommendations

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.



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The woman described in the vignette should bereassured that inflammatory papules and pustulesusually respond to therapy and resolve without scar-ring and that rhinophyma rarely develops in wom-en. She should be advised to apply a sunscreen dailythat provides protection against both ultraviolet Aand ultraviolet B irradiation and to avoid using irri-tating topical products. Treatment should be initi-ated with 100 mg of doxycycline or 100 mg of mi-nocycline daily for a period of 6 to 12 weeks. Thisshould be followed by maintenance therapy withazelaic acid, topical metronidazole, or a sodium sul-

facetamidesulfur preparation applied twice dailyfor six months and then gradually discontinued,as outlined above. Laser therapy should be consid-ered for residual, prominent telangiectatic vessels.The oral antibiotic is likely to help the patients oc-ular symptoms, and she should also be advised toclean her eyelids with warm water twice daily andto use artificial tears. Referral to an ophthalmolo-gist should be considered if her ocular symptomspersist.

Dr. Powell reports having received speaking fees from GaldermaLaboratories, Bradley Pharmaceuticals, and Dermik Laboratories.

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a double-blind trial. Br J Ophthalmol 1982;66:386-8.50. Quarterman MJ, Johnson DW, AbeleDC, Lesher JL Jr, Hull DS, Davis LS. Ocularrosacea: signs, symptoms, and tear studiesbefore and after treatment with doxycycline.Arch Dermatol 1997;133:49-54.51. Powell FC. Whats going on in rosacea?J Eur Acad Dermatol Venereol 2000;14:351-2.52. Ernst E. The use of complementary ther-apies by dermatological patients: a systemat-ic review. Br J Dermatol 2000;142:857-61.Copyright 2005 Massachusetts Medical Society.

clinical trial registration

The Journal encourages investigators to register their clinical trials in a public trials registry. The members of the International Committee of Medical Journal Editors

plan to consider clinical trials for publication only if they have been registered (see N Engl J Med 2004;351:1250-1). The National Library of Medicines

www.clinicaltrials.gov is a free registry, open to all investigators, that meets the committees requirements.



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