american journal of clinical dermatology

REVIEW ARTICLE

Perioral Dermatitis: A Review of the Conditionwith Special Attention to Treatment Options

Therdpong Tempark • Tor A. Shwayder

Published online: 13 March 2014

� Springer International Publishing Switzerland 2014

Abstract Perioral dermatitis is a common acneiform

facial eruption found in both adults and children. Its vari-

ants are periorificial and granulomatous periorificial der-

matitis. The etiology of perioral dermatitis remains

unknown; however, topical corticosteroid use on the face

commonly precedes the manifestation of this condition.

There are an overwhelming number of treatment options

for perioral dermatitis, and the options in children are

slightly different from those in adults for both systemic

medications and topical treatment. This article provides a

literature review of the various applicable treatments

available based on the level and quality of the evidence by

the US Preventive Service Task Force. Oral tetracycline

reveals the best valid evidence. However, if the patient is

less than 8 years old, then this oral therapy may not be

suitable. Topical metronidazole, erythromycin, and pime-

crolimus also represent effective treatment choices with

good evidence. Topical corticosteroid use is common in

these cases and the question of whether it is a good treat-

ment or a cause remains unanswered. Corticosteroid cream

can improve the clinical picture, but there is a risk of

rebound when treatment is stopped. We propose a treat-

ment algorithm to assist dermatologists, pediatric derma-

tologists, and general practitioners encountering this

condition.

1 Introduction

Perioral dermatitis is a chronic dermatosis that is usually

characterized by non-itchy, erythematous papules or pap-

ulopustules around the perioral area. If the lesions involve

perinasal and periorbital areas, the term ‘periorificial der-

matitis’ is often, but not always, used [1].

Perioral dermatitis is often found among women

between the ages of 16 and 45 years. However, it has also

been reported to occur among children between the ages of

7 months and 13 years [2]. The frequency of occurrence of

perioral dermatitis is not significantly different between the

sexes or between ethnic groups [3].

Because the knowledge and recognition of this

recalcitrant disease is potentially important, we

reviewed and summarized several articles, aiming to

enhance such literature, experiences, knowledge, and

recognition for the best and most appropriate manage-

ment under the care of both dermatologists and general

practitioners.

1.1 Literature Review

The following databases were searched up to January 2014:

the US National Library of Medicine (PubMed), Ovid

MEDLINE, and Scopus. Search terms included ‘perioral

dermatitis,’ ‘periorificial dermatitis,’ and ‘treatment of

perioral dermatitis.’

The topic and abstracts of original articles, reports,

documents, and review articles in English, including male

or female patients of any ages or ethnic origins, were

screened and analyzed separately by the authors. Related

articles and reports on topics such as treatment of perioral

dermatitis or periorificial dermatitis were included and full

texts were reviewed.

T. Tempark (&)

Department of Pediatrics, Faculty of Medicine,

Chulalongkorn University, Sor Kor 11th Building,

Pathumwan, Bangkok, Thailand

e-mail: [email protected]

T. Tempark � T. A. Shwayder

Department of Dermatology, Henry Ford Hospital,

Detroit, MI, USA

Am J Clin Dermatol (2014) 15:101–113

DOI 10.1007/s40257-014-0067-7

We found English references from Scopus (883), Pub-

Med (428), and Ovid MEDLINE (266) databases; 88 arti-

cles were identified as related to our findings.

2 Pathogenesis/Etiology

The exact pathogenesis of this condition is unknown.

Topical corticosteroid use on the face commonly precedes

the manifestation of this condition [4], and risk factors

include long-term use of corticosteroids [5]. If perioral

dermatitis has been diagnosed, corticosteroid cream can

improve the clinical picture, but carries a risk of rebound

when the cream is stopped. It is not definitely known how

topical steroids may lead to perioral dermatitis. The pre-

sumptive pathogenesis is direct influence on the piloseba-

ceous unit or alteration of the follicular microflora, with a

subsequent increase in proliferation and metabolic activity

of infectious agents and skin biota [6, 7].

There is a long list of possible causes for perioral der-

matitis such as infectious agents (Demodex spp. [2, 8],

Candida albicans [6], Fusiform bacteria [9]), medication

(topical corticosteroids [10], inhaled corticosteroids [11–

13], oral corticosteroids [14], tacrolimus, pimecrolimus),

fluoride and anti-tartar toothpaste [15, 16], cosmetics/

moisturizers [17, 18], sunscreens [19], dental fillings [20],

orthognathic surgery [21], and chewing gum [22]. How-

ever, it should also be noted that there is another group of

factors associated with perioral dermatitis such as hor-

mones (premenstrual flare, contraceptive pills, and preg-

nancy [2]), skin barrier dysfunction (atopic dermatitis) [23,

24], systemic corticosteroids in renal transplantation [25],

Crohn’s disease [26, 27], and myasthenia gravis [28].

Hence, it is reasonable to assume that perioral dermatitis is

a combination of the person’s genes, environment, and

response to multiple different stimuli.

3 Clinical Presentation

Perioral dermatitis is characterized by a facial eruption of

erythematous papules, papulovesicles, and/or papulopus-

tules around a narrow zone of the perioral area and spar-

ingly around the vermilion border of the lips. Erythematous

papules and papulopustules may occur around the chin,

perinasal, and perioral area. The lesions are usually

accompanied by a diffused erythema and scaling. Burning

sensations have been reported in the literature to occur

more frequently than pruritus [29]. However, in our clinical

experience of more than 25 years, none of our pediatric

patients have reported a burning sensation. There is a wide

range of severity and chronicity in this disease.

A variant of perioral dermatitis is frequently detected

around the perioral, perinasal, and periorbital areas in

prepubertal children [30] (Figs. 1, 2), whereas extra-facial

granulomatous papules and typical periorificial papules

have been reported to occasionally occur around the neck,

trunk, extremities, and the genital area [30, 31]. Histopa-

thology results indicate that the upper dermal and perifol-

licular granuloma are infiltrated by lymphocytes. Some

investigators term this variant as ‘granulomatous periori-

ficial dermatitis’ [32].

Fig. 1 A 12-year-old Black female who has had perioral dermatitis

for the past 2–3 years. Note the monomorphic papular component

around the mouth, the side of the nose, and the inner eyelids of both

the upper and lower eyes

Fig. 2 A 6-year-old Hispanic male who has had perioral dermatitis

for the past year. More erythematous papules noted more prominently

around the mouth

102 T. Tempark, T. A. Shwayder

4 Histopathology

Histopathology examinations commonly show non-specific

inflammation with varied amounts of perifollicular or

perivascular lymphohistiocytic infiltration [2] (Fig. 3).

Perifollicular sarcoid-like granuloma and lymphocytic

infiltration [32, 33] are sometimes found in perioral

dermatitis.

5 Differential Diagnosis

The differential diagnosis for perioral dermatitis are the

facial dermatoses, which can be broken down into various

other forms such as acne, contact dermatitis, seborrheic

dermatitis, rosacea, sarcoidosis, eruptive syringoma, and

lupus miliaris disseminatus faciei (LMDF) [2, 34–36].

Rosacea usually occurs in adults. The characteristics of

rosacea are facial erythema; telangiectasia; and flushing

papules and pustules around the cheeks, chin, and central

face (nasolabial area) [37, 38]. The nose and cheeks are the

most common sites afflicted. It is difficult to differentiate

granulomatous rosacea from sarcoidosis and granuloma-

tous perioral dermatitis (GPD) [39–41].

Sarcoidosis shares several features with rosacea. Phys-

ical examination reveals red-brown papules on the face and

lips. Sarcoidosis can also occur in the eye, causing uveitis,

retinitis, and keratitis. The lesions may even extend to the

neck and trunk area. This condition is often associated with

systemic findings such as fatigue, joint pain, weight loss,

and pulmonary symptoms [34, 38].

GPD is characterized by groups of papules, pustules,

and diffused erythema around the mouth, eyes, and nose in

prepubertal children. It may be difficult to differentiate this

from non-GPD by clinical findings alone. Histopathology

is needed in diagnosing this variant.

LMDF is a rare chronic caseating granulomatous con-

dition with erythematous or flesh-colored papules distrib-

uted symmetrically across the eyelids, nose, upper lips, and

in the central area of the face [42]. The lesions can persist

for 1–2 years with spontaneous healing and often resulting

in scarring [34, 42]. However, it should be noted, that in

our experience, we have never witnessed scarring in chil-

dren with perioral dermatitis. It should be noted that some

investigators have proposed that LMDF is the same as GPD

because of its clinical histopathology [34].

Facial Afro-Caribbean Eruption (FACE) is a sarcoid-

like granulomatous dermatosis. This condition is often seen

in children with dark-colored skin. The characteristic fea-

ture is flesh-colored monomorphic papules in the perioral,

perinasal, and periocular area, particularly around the

upper eyelids and outer helix of the ears [43]. Histological

tests usually reveal a granulomatous infiltration that often

results in a differential diagnosis for sarcoidosis [44]. Some

investigators have proposed that FACE is a variant of

rosacea [43].

Table 1 details the different terminologies used for

perioral dermatitis and its variants.

An algorithm approach to investigate and manage per-

ioral dermatitis is shown in Fig. 4.

History and physical examinations are the most helpful

tools in diagnosing perioral dermatitis. Additional investi-

gations using potassium hydroxide (KOH), skin scrapings

for Demodex spp. [8], bacterial culture from pustular

lesions [9], patch testing for suspected allergens [45], and

skin biopsies are all optional and can be conducted at the

discretion of the attending physician.

6 Treatment

There are many treatment options available for perioral

dermatitis based on the theoretical etiologies of the disease.

However, most of the treatment protocols have mainly

been developed through trial and error.

Topical corticosteroids are often used as the first-line

therapy for perioral dermatitis. The one exception is in

patients whose perioral dermatitis developed while using

topical steroid creams. For these patients, the use of topical

steroid creams may be the ‘cause’ of the disease, and

Fig. 3 Biopsy from a patient clinically similar to the boy in Fig. 2,

taken from the chin. Pathology shows superficial perivascular mixed

inflammatory infiltrates with perifollicular accentuation

Perioral Dermatitis 103

discontinuation of the creams is recommended. We place

‘cause’ in quotation marks because whether topical steroids

cause or cure perioral dermatitis is unanswered in the lit-

erature (see below). It should be noted that, upon discon-

tinuation of the topical corticosteroid, symptoms will

reappear within the first few weeks due to rebound flares.

Therefore, it is important to slowly reduce the use of the

topical corticosteroid over a span of several weeks to

prevent this rebound flare from occurring [46]. Aside from

topical corticosteroids, anti-tartar toothpastes have also

Perioral lesion

Perioral dermatitis(spare vermilion border)

Infection Irritant / Allergy Others Idiopathic

-Demodex-Candida-Fusiform bacteria

-Topical CS/ Inhale CS-Toothpaste: fluoride, tartar-Cosmetics/Moisturizer-Sunscreen-Dental filling-Orthognathic surgery-Chewing gum

-Hormonal factors-Pregnancy-Skin barrier dysfunction: AD-Drug : contraceptive pills, systemic CS

Others: lip dermatitis, cheilitis(involve vermilion border or commissure of lip)

Allergic contact dermatitis Irritant contact dermatittis Atopy

Scraping, KOH, culture

Patch test History taking

Skin biopsy

Treat infection Avoid suspected cause Treat cause Treatment

Patch test / Photo patch test

Avoid and treatment

Treat atopy and 2nd

infectionAvoid and treatment

Fig. 4 Algorithm of approach, management, and investigation of perioral dermatitis. AD atopic dermatitis, CS corticosteroid, KOH potassium

hydroxide

Table 1 Differential diagnosis of perioral dermatitis and its variants

Term Age group Area involvement Clinical features Histopathology Remarks

Perioral

dermatitis

(POD)

Children,

young

women

Perioral Erythematous papules,

papulovesicles, and

papulopustules on

erythematous base

Perifollicular lymphocytic

infiltration, perivascular

infiltration

No scarring

Often referred to as a

juvenile form of

rosacea

Granulomatous

periorificial

dermatitis

(GPD)

Prepubertal Perioral, perinasal,

periorbital, and/or

extrafacial

Dome-shaped

erythematous, yellow-

brown papules (lack of

pustules)

Perifollicular granulomatous

infiltration is usually

detected on the upper half of

the body

Results in some

scarring

Some authors suggest

that this is a variant

of granulomatous

rosacea

Lupus miliaris

disseminatus

faciei

(LMDF)

Adolescent,

adult

Symmetrical across

eyelids, nose, upper

lips (central area of

face)

Erythematous/flesh-

colored papules

Multiple, 1–3 mm in size


lymphohistiocytic

infiltration and occasionally

some neutrophils

The most characteristic

feature is the epithelioid cell

granuloma with central

caseated necrosis

Results in scarring


this is a variant of

granulomatous

rosacea

Not related to

tuberculosis

Facial Afro-

Caribbean

eruption

(FACE)

Black

children

Perioral, periorbital,

perinasal, especially

upper eyelid, outer

helix of the ear

Flesh-colored

monomorphic papules

(no pustules, erythema,

comedone)


infiltration

No scarring


this is a variant of

rosacea


been reported to aggravate perioral dermatitis [15, 16].

Even the paste itself and its occlusive effect have been

reported to somehow precipitate this eruption [18].

On the other hand, if topical contacts are suspected as

the cause of perioral dermatitis, then it is probably prudent

to discontinue all topical applications [2] including, but not

limited to, topical corticosteroids, cosmetics, moisturizers,

and sunscreens. Instead, the physician should recommend

that patients use bland emollients without any additives or

preservatives, if possible. It has been shown that occlusive

topical creams or ointments can sometimes somehow pre-

cipitate this eruption [18]. Lastly, two separate reports have

shown that topical corticosteroids used for the treatment of

atopic dermatitis caused the children’s perioral dermatitis

[24, 47].

Clinical trials evaluating different treatment protocols

for perioral, periorificial, and granulomatous periorificial

dermatitis are detailed in Tables 2 and 3. The level and

quality of the different treatment regimens are evaluated in

Table 4 based on the grading systems reported in the

documents issued by the US Task Force on Preventive

Health Care (retrieved 20 December 2013 from http://

www.uspreventiveservicestaskforce.org/uspstf/grade.htm).

Information such as the level and quality of the evidence

based on the study design, risks, and benefits of the med-

ications were used to develop the grading scale shown in

Table 4.

6.1 Oral Tetracycline

Oral tetracycline is one of the treatments of choice for

perioral dermatitis. It is used in children older than 8 years

because it can severely stain developing teeth. The exact

mechanism of action is unknown.

The performance and efficacy of oral tetracycline has

been well documented. When oral tetracycline was com-

pared with topical metronidazole in a prospective, double-

blind, randomized, multicenter trial, it was shown that oral

tetracycline was significantly more effective than topical

metronidazole [60].

Another prospective, randomized therapeutic study

compared the effectiveness of oral tetracycline to that of a

placebo, and showed that oral tetracycline was effective in

reducing the symptoms. In the same study, another anti-

biotic, topical erythromycin, was also compared with the

placebo and yielded the same results as the oral tetracy-

cline. However, when oral tetracycline was compared with

topical erythromycin, it was shown that neither of the

antibiotics outperformed each other [62].

Many studies evaluated the performance of oral tetra-

cycline used with other various topical medicines. All of

these studies showed a positive effect; however, because

there were many different variables in the mix, it was

difficult to definitively conclude whether oral tetracycline

outperformed the other medications. The common

denominator in all of the studies was oral tetracycline

(Table 2).

The dose of tetracycline varied from 250 mg twice daily

to four times daily [55] and 500 mg twice daily in severe

cases [42, 73]. The duration of the treatment varied

according to the response, which was usually around

4–8 weeks.

Adverse short-term effects (e.g. gastrointestinal upset,

diarrhea, and rarely photosensitivity) and long-term effects

(rare elevated liver function tests) should be discussed with

the patient thoroughly before initiating treatment.

6.2 Oral Erythromycin/Oral Macrolides

Pregnant women and pediatric patients are not allowed to

take oral tetracycline. In these cases, an alternative such as

oral erythromycin may be used. There are no efficacy data

for oral erythromycin from randomized controlled trials.

Nevertheless, several publications have reported the suc-

cessful use of oral erythromycin. For example, Urbatsch

et al. [30] reported that oral erythromycin administered

concomitantly with another topical medication was effec-

tive in pediatric patients with extra-facial and generalized

granulomatous periorificial dermatitis. In another study,

oral erythromycin 250 mg administered two to three times

daily was less effective than tetracycline 250 mg admin-

istered twice daily, yet it still worked to some degree [78].

In two further studies, erythromycin 500 mg/day has been

reported to be effective [74]. The time to cure varied from

1 to 12 months [30, 74].

6.3 Oral Doxycycline/Oral Minocycline

Doxycycline and minocycline are second-generation tet-

racyclines. These medications exhibit greater bioavail-

ability and absorption and broader anti-bacterial activity

than tetracycline [79]. Systemic medications have been

used in multiple dermatologic conditions, including acne,

acne rosacea, and perioral dermatitis.

A few cases have reported using minocycline [34] or

doxycycline [13] for the treatment of perioral dermatitis. It

is difficult to deduce the effectiveness of minocycline and

doxycycline because they were co-administered with other

topical medications. Cure time could not be ascertained, as

these studies were not randomized, double-blinded, pla-

cebo-controlled trials. Side effects of minocycline have

been reported to possibly include pseudotumor cerebri,

blue-gray hyperpigmentation, vertigo, and lupus-like syn-

drome in female patients. Doxycycline may cause gastro-

intestinal upset and esophageal irritation, especially when

taken as doxycycline hyclate.


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s

:O

ral

PL

reso

lved

afte

r8

0d

ays

Sig

nifi

cant

dif

fere

nce

was

det

ecte

db

etw

een

3g

rou

ps

[62]

Ser

ies

Topic

alM

ET

74–12

16

wee

ks

Yes

No

Res

olv

edin

12–24

wee

ks

No

recu

rren

cein

24

month

saf

ter

txco

mp

lete

d[6

3]

Rep

ort

Topic

alad

apal

ene

132

4w

eeks

Yes

Yes

Res

olv

edN

ore

curr

ence

in8

month

saf

ter

txco

mp

lete

d[2

3]

Ser

ies

To

pic

alE

RY

oin

tmen

t(E

RY

,T

iO2,

talc

,p

araf

fin

,et

c.)

10

8–

77

(med

ian

48

)

12

wee

ks

Yes

Yes

Pap

ule

cou

nt

reso

lved

in3

–1

2w

eeks

(5w

eek

s)F

ailu

red

etec

ted

in1

0–

30

%w

ho

use

dto

pic

altx

[64]

Rep

ort

Topic

alaz

elai

cac

id10

32–65

2–6

wee

ks

Yes

Yes

Res

olv

edin

2–6

wee

ks

No

recu

rren

cein

4–

10

mon

ths

afte

rtx

com

ple

ted

[65]

Ser

ies—

sele

ctiv

esp

lit

face

�:

AL

AP

DT

(1–

4ti

mes

/w

eek

)

�:

To

pic

alcl

ind

amy

cin

14

10

–7

0(m

ean

36

.5)

4w

eeks

Yes

No

Ery

them

ao

rpal

pab

lele

sions,

mea

ncl

eara

nce

of

AL

AP

DT

(92

.1%

)[

top

ical

clin

dam

yci

n(8

0.9

%)

Sig

nifi

cant

dif

fere

nce

det

ecte

db

etw

een

2g

rou

ps

[66]

Rep

ort

Topic

alP

IM1

22

2w

eeks

Yes

–R

esolv

edU

nder

lyin

gC

D

No

recu

rren

cein

4m

on

ths

afte

rtx

com

ple

ted

[27]

Ran

do

miz

ed,

do

uble

-bli

nd

ed,

sing

le-c

ente

r

:T

op

ical

PIM

(20

)

:T

op

ical

veh

icle

crea

m(2

0)

40

18

–7

04

wee

ks

Yes

Yes

[5

0%

PO

DS

Isc

ore

dec

reas

edfr

om

bas

elin

e

:S

core

top

ical

PIM

\v

ehic

le

Ass

esse

db

yP

OD

SI

[67]

Ran

do

miz

ed,

do

uble

-bli

nd

ed,

mult

icen

ter

:T

op

ical

PIM

(60

)

:T

op

ical

veh

icle

crea

m(6

4)

12

4[

18

4w

eek

sY

esY

esP

OD

SI

sco

red

ecre

ased

for

more

than

50

%at

bas

elin

e

:S

core

top

ical

PIM

\v

ehic

le

Ass

esse

db

yP

OD

SI

Sig

nifi

cant

dif

fere

nce

det

ecte

db

etw

een

2g

rou

ps

[68]

Rep

ort

Ora

ld

ox

ycy

clin

e?

top

ical

clin

dam

yci

n/M

ET

11

38

wee

ks

––

Res

olv

edA

uth

ors

consi

der

eddis

ease

cause

db

yin

hal

edC

S[1

3]

Rep

ort

aT

opic

alM

ET

16

16

wee

ks

Yes

Yes

Res

olv

edM

ild

PIH

[69]

Ser

iesa

To

pic

alaz

elai

cac

id1

03

–1

2(m

ean

7.7

)

4–8

wee

ks

Yes

Yes

Res

olv

edin

4–8

wee

ks

(5.4

wee

ks)

No

recu

rren

cein

2–8

month

saf

ter

txco

mp

lete

d[7

0]

Rep

ort

Ora

lce

fcap

ene

piv

oxil

hy

dro

chlo

rid

e3

10–37

2–5

wee

ks

Yes

–R

esolv

edin

2–5

wee

ks

Iden

tify

fuso

bac

teri

aby

usi

ng

tap

e-st

rip

pin

gto

luid

ine

blu

em

eth

od

[71]

AL

AP

DT

5am

inole

vuli

nic

acid

and

photo

dynam

icth

erap

y,

CS

cort

icost

eroid

,C

DC

rohn

’sd

isea

se,

ER

Yer

yth

rom

yci

n,

F/U

foll

ow

-up

,H

Ch

yd

roco

rtis

on

e,M

ET

met

ron

idaz

ole

,P

IHp

ost

-in

flam

mat

ory

hy

per

pig

men

tati

on

,P

IMp

imec

roli

mu

s,P

Lpla

cebo,

PO

DS

Iper

iora

lder

mat

itis

sever

ity

index

,p

tsp

atie

nts

,T

ET

tetr

acycl

ine,

TiO

2ti

tan

ium

dio

xid

e,tx

trea

tmen

ta

Per

iori

fici

ald

erm

atit

is


6.4 Oral Isotretinoin

We found only one report on the use of isotretinoin for the

treatment of GPD [39]. This patient had tried various other

combination therapies with no success. As a result, the

investigator decided to prescribe 0.7 mg/kg/day isotreti-

noin for 20 weeks; after which the patient was cured of

GPD. However, the investigator pointed out that the results

obtained from isotretinoin could actually be due to the

spontaneous recovery of the patient who had received a

series of combination therapies. This patient had used oral

tetracycline for 5 months in combination with oral metro-

nidazole for 2 months, and several other topical medica-

tions. Other medications the patient had tried were 2 %

erythromycin solution, 0.05 % tretinoin cream, and 5 %

benzoyl peroxide gel [39]. If the physician should decide to

prescribe isotretinoin to a patient, it is important to monitor

the long-term adverse effects, especially in sexually active

women regarding pregnancy and potential adverse effects

on the fetus.

6.5 Oral Cefcapene Pivoxil Hydrochloride

Only one report concerned the treatment of perioral der-

matitis using cefcapene pivoxil [71]. Three Japanese

patients with this condition had been examined for Fuso-

bacteria using the tape-stripping toluidine blue method

both before and after treatment. Fusobacteria was positive

before treatment and became negative within 3 weeks after

treatment with this medication. These patients showed

Table 3 Different treatment regimens reported for granulomatous periorificial dermatitis

Study

design

Regimen No. of

pts

Age (y) Treatment

duration

(weeks)

Stop

CS

Stop

cosmetic

Endpoint/

outcome

Remark References

Report Multiple txs 5 3–11 Not clear – – Spontaneously

resolved

– [32]

Series Oral ERY 2 9–10

(mean

9.5)

12 – – Resolved FACE [43]

Report Oral isotretinoin 1 23 20 – – Resolved Resulted in pitted,

atrophic scarring

No recurrence in

6 months after tx

completed

[39]

Report Topical MET 3 7.7 14 – – Resolved – [72]

Report Topical MET 1 9 12 Yes Yes Resolved – [44]

Series Oral ERY/macrolide

? topical antibiotics/CS

(mixture of therapies -

no consistent regimens)

8 2–12 2–24 – – Resolved Extrafacial and

generalized GPD

[30]

Report Oral TET ? oral CS ?topical clindamycin

1 12 [3 – – Resolved in

[3 weeks

– [42]

Report Oral

minocycline ? topical

TAC

1 11 3 – – Resolved No recurrence in

2 months after tx

completed

[34]

Report Oral TET ? topical MET 1 14 3 Yes – Resolved No recurrence in

12 months after tx

completed

[73]

Report Oral ERY 1 11 52 – – Resolved – [74]

Report Topical TAC 1 11 [2 – – Resolved – [75]

Report Oral ERY ? topical MET 1 2 16 – – Resolved GPD with extrafacial

lesions

[76]

Report Topical MET ? oral MET 1 9 4 Yes – Resolved GPD

No recurrence in

12 months after tx

completed

[77]

CS corticosteroid, ERY erythromycin, FACE facial Afro-Caribbean eruption, GPD granulomatous periorificial dermatitis, MET metronidazole,

pts patients, TAC tacrolimus, TET tetracycline, tx treatment


improvement in 1–2 weeks and were cured after

2–5 weeks without adverse effects during treatment.

Cefcapene pivoxil hydrochloride, a b-lactam antibiotic,

is effective on Fusobacteria, which is presumed to be a

cause of perioral dermatitis. Although this report reveals

the effectiveness of this medication, further studies should

be performed in cases where tests for Fusobacteria are

absent or negative.

6.6 Topical Metronidazole

The presumptive mechanisms of action for topical metro-

nidazole for the treatment of perioral dermatitis are its

ability to suppress the activity of the bacterial skin flora,

and counter the activities of Demodex spp. and inflamma-

tion. The latter is by way of reducing hydrogen peroxide

into hydroxyl radicals [72]. Various concentrations

(0.75–2 %) and preparation forms of metronidazole (gel,

cream) have been investigated. Topical metronidazole has

been reported to be effective with or without oral medi-

cation. 1 % metronidazole cream used for 8 weeks was

shown to be effective [60]. Similarly, but at the lower

concentration of 0.75 %, metronidazole gel used for

14 weeks resolved the symptoms [72]. However, when a

higher concentration of 2 % was used, the time to cure was

a lot longer (16 weeks.) Higher concentrations of the

medication did not decrease the time to cure [63].

Generally, topical metronidazole was found to be less

effective than oral tetracycline [60] and therefore is used as

optional medication for the treatment of perioral, periori-

ficial dermatitis in pediatric patients. The mean time to cure

varied from 8 to 16 weeks [44, 60, 63, 69, 72].

6.7 Topical Erythromycin

According to one randomized prospective therapeutic

study, 1 % topical erythromycin was effective after

7 weeks of use, whereas for oral tetracycline it was less

than 6 weeks [62]. Topical erythromycin was less effective

than oral tetracycline. In another report, 1.5 % topical

erythromycin solution was used concomitantly with topical

hydrocortisone valerate cream of 0.2 % to prevent acute

rebound flare of the disease while stepping down from

higher potency steroid creams [58]. The time to cure with

this combination therapy was 2–8 weeks (mean 5 weeks)

[58]. It should be noted that systemic oral erythromycin

had a greater efficacy than the topical treatment [78].

Having said this, topical erythromycin treatment is often

used as the first-line medication because it has no gastro-

intestinal side effects, unlike oral erythromycins.

6.8 Topical Clindamycin

A few studies have investigated the use of topical clinda-

mycin. Topical clindamycin is often used concomitantly

with oral antibiotics [13]. One report used topical clinda-

mycin as the control medication for split face photody-

namic therapy (PDT) [66]. The efficacy and mean cure

times were unclear from this article. The rationale for the

use of topical clindamycin for the treatment of perioral

dermatitis may have derived from its effectiveness in adult

rosacea patients.

6.9 Topical Pimecrolimus

Two 4-week randomized, double-blind, vehicle-controlled

(single and multicenter) studies showed that topical pime-

crolimus was effective in improving the Finlay’s Derma-

tology Life Quality Index (DLQI) when the Perioral

Dermatitis Severity Index (PODSI) decreased more than

50 % compared with baseline [67, 68]. However, only the

results from the multicenter study showed statistical sig-

nificance [68].

The presumptive pathomechanism of topical pimecrol-

imus is its ability to block the induction of pro-inflamma-

tory cytokines by the nuclear factor of activated T cells

(NFAT). This blockage suppresses the T-cell responses to

proteins and inflammatory pathogens [67, 80]. Because of

Table 4 Authors’ evaluation of the different treatments available

according to the level and quality of evidence reporteda

Medication Grades for level and

quality of evidence

Systemic medication

Tetracycline IA

Erythromycin II-3C

Doxycycline/minocycline IIIC

Cefcapene pivoxil hydrochloride IIIC

Isotretinoin IIID

Topical medication

Metronidazole IB

Erythromycin IB

Pimecrolimus IB

Clindamycin II-3B

Azelaic acid II-3B

Sulfacetamide/sulfur II-3C

Tacrolimus IIIB

Adapalene IIIC

Corticosteroid IIIC

a Grading scales for levels of clinical service and evidence about the

effectiveness of the treatments were based on the documents issued

by the US Preventive Service Task Force (Retrieved 20 December

2013 from http://www.uspreventiveservicestaskforce.org/uspstf/

grades.htm)


http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm

http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm

this anti-inflammatory effect, and because it is a non-ste-

roid-based cream, pimecrolimus is suitable as an optional

treatment for corticosteroid-induced perioral dermatitis

[68]. Pimecrolimus does not have an effect on Demodex

spp. nor does it have any vasoactive properties [81, 82].

Pimecrolimus is generally well tolerated. A small number

of patients have complained of a burning or smarting

sensation upon application [68].

6.10 Topical Tacrolimus

There were only two reports of topical tacrolimus in the

literature. One report was from a patient with granuloma-

tous periorificial dermatitis [75]. In the other reported case,

the patient used topical tacrolimus concomitantly with oral

minocycline [34]. For both reports, the lesions resolved in

2 weeks when the topical tacrolimus was used and in

3 weeks if the topicals were used with oral antibiotics. The

presumptive mechanism of action is the same as that of

pimecrolimus.

6.11 Topical Adapalene

The rationale for the use of adapalene may derive from the

use of systemic oral isotretinoin for the treatment of

granulomatous periorificial dermatitis [39]. Jansen [23]

reported on the successful use of topical adapalene in a

patient with perioral dermatitis. The dermatitis resolved in

4 weeks.

This medication is a synthetic naphthoic acid derivative

that causes fewer skin irritations than retinoic acid. The

investigators suggested that the most likely pathomecha-

nism of adapalene is its anti-inflammatory activity or

ability to interfere with the functions of polymorphonuclear

leukocyte and its arachidonic acid metabolism [23].

6.12 Topical Azelaic Acid

Two reports covered the use of topical azelaic acid, both

from open-label studies. One report was obtained from

adult patients with perioral dermatitis [65] and the other

from pediatric patients with periorificial dermatitis [70].

The cure time for the adult and pediatric patients were 2–6

and 4–8 weeks, respectively.

The exact mechanism of action of azelaic acid is

unknown, although it has been suggested that its antibac-

terial and anti-inflammatory effect and immunomodulatory

activity could prevent the neutrophilic pro-inflammatory

reactive oxygen species from being released [83]. As a

result of this suppression, inflammatory lesions and ery-

thema disappeared [83].

The common adverse effects reported were transient

burning sensation, increased erythema, and scaling after

application, especially in the first 2 weeks of treatment [65,

70]. Additional clinical randomized, double-blind, placebo-

controlled and comparative studies are warranted to con-

firm the efficacy of this topical medication.

6.13 Topical Sulfacetamide and Sulfur

Sodium sulfacetamide 10 % and sulfur 5 % combination

is available as a cream, lotion, suspension, and cleanser.

The rationale for the use of this medication may derive

from its use for the treatment of acne, rosacea, and se-

borrheic dermatitis [84–87]. One report had combined this

topical medication concomitantly with another topical

hydrocortisone lotion for the treatment of perioral der-

matitis [53]. The efficacy of this combination could not be

ascertained.

The presumptive mechanism of sodium sulfacetamide is

its anti-microbial and anti-inflammatory properties [88].

Sulfur is known as a mild keratolytic agent [84]. The most

common side effect of this combination therapy is its

unpleasant odor. Serious side effects have not been

reported.

7 Summary and Recommendations

There were many reports for the treatment of perioral,

periorificial, and granulomatous periorificial dermatitis but

none of the medications appeared to be a clear winner in

completely curing the disease. Therefore, a practical

approach in treating perioral dermatitis should be estab-

lished. First, the physician should try to ascertain whether

there are any aggravating factors involved that can be

teased out from the patient’s history. Oral tetracycline is

the first line of treatment for perioral dermatitis and its

variants for patients older than 8 years. According to the

grades, level, and quality of evidence, oral tetracycline

reveals the best valid evidence (randomized, double-blind,

multicenter, randomized report). The number of patients

in several studies increases the reliability of its efficacy.

However, if the patient is younger than 8 years, this oral

therapy may not be suitable. Instead, this regimen can

become problematic because of its usual side effects,

week upon week of dosing, and patient or parental fatigue

in administering oral medicines without obvious and

quick clearing of the skin. Topical metronidazole, eryth-

romycin, and pimecrolimus are effective treatments (ran-

domized, double-blind, multicenter/single center, case

series/report). These topical agents have been used alone

and/or combined with oral treatments in previous studies.

Hence, we recommend that physicians use topical treat-

ments that have been evaluated to be effective and rotate

them every 6–8 weeks if the patient fails to respond. It is


not uncommon for many physicians to resort to using

several low-potency topical corticosteroids, topical

immune modulators, topical sulfurs, topical erythromycin,

topical clindamycin, topical metronidazole, and others in

succession. Oral erythromycin can certainly be used in

children.

In addition to discontinuing any possible items that may

aggravate the disease, appropriate care should be taken

according to the severity, age, sex, and individual concerns

of the patient. Above all, it is the duty of the physician to

reassure the patients at each visit that this condition is

neither infectious nor fatal. Based on our clinical experi-

ence and reported evidence-based treatment for perioral

dermatitis, we have developed a treatment algorithm that

we hope will assist physicians encountering patients with

this disease (Fig. 5).

Statement of Funding None.

Conflict of Interest Disclosures Dr. Tor A. Shwayder: None.

Dr. Therdpong Tempark: None.

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