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dermatologia
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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: therdpmhu@yahoo.com
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
Perifollicular granulomatous
lymphohistiocytic
infiltration and occasionally
some neutrophils
The most characteristic
feature is the epithelioid cell
granuloma with central
caseated necrosis
Results in scarring
Some authors suggest
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)
Perifollicular granulomatous
infiltration
No scarring
Some authors suggest
this is a variant of
rosacea
104 T. Tempark, T. A. Shwayder
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.
Perioral Dermatitis 105
Ta
ble
2D
iffe
ren
ttr
eatm
ent
reg
imen
sre
po
rted
for
per
iora
lan
dp
erio
rifi
cial
der
mat
itis
.If
ap
aper
uti
lize
dm
ore
than
on
ere
gim
en,
the
colo
nsy
mb
ol
(:)
isu
sed
tore
pre
sen
tea
chth
erap
yo
rar
m
Stu
dy
des
ign
Reg
imen
No
.o
fp
atie
nts
Ag
e(y
)D
ura
tio
no
ftx
Sto
pC
SS
top
cosm
etic
En
dpo
int/
ou
tco
me
Rem
ark
Ref
eren
ces
Rep
ort
Ora
lan
tim
alar
ials
?to
pic
als
92
11
–4
8(m
ean
26
.4)
No
tcl
ear
No
No
93
.5%
clea
red
63
.2%
had
no
recu
rren
ceaf
ter
4–
23
mon
ths’
tx[4
8]
Rep
ort
Ora
lT
ET
?P
L3
–6–8
wee
ks
Yes
No
Res
olv
ed–
[49]
Rep
ort
Ora
lT
ET
?v
ario
us
top
ical
s2
91
8–
39
(mea
n2
7)
8–12
wee
ks
Yes
No
Res
olv
edV
ario
us
topic
als
wer
eal
tern
ativ
ely
use
d[5
0]
Rep
ort
Ora
lT
ET
73
28
Sev
eral
mon
ths
Yes
No
Dat
an
ot
clea
r–
[51]
Sin
gle
bli
nd
edtr
ial
Ora
lT
ET
?to
pic
alC
S8
30
2–
5w
eeks
(no
tcl
ear)
Yes
No
Dat
an
ot
clea
r–
[52]
Rep
ort
:O
ral
TE
T?
topic
als
(56
)
:T
opic
alsu
lfac
etam
ide-
sulf
ur-
HC
loti
on
(25
)
:V
ario
us
topic
als
(25)
95
(11
lost
toF
/U)
2.5
–6
0(m
edia
n2
9)
[4
wee
ks
No
Yes
:O
ral
TE
T?
topic
als
reso
lved
in1
0d
ays–
4w
eek
s
:T
op
ical
s—d
ata
no
tcl
ear
:V
ario
us
top
ical
s—re
solv
edin
[4
wee
ks
Mo
istu
rizi
ng
pro
duct
sw
ere
indic
ated
toca
use
the
dis
ease
[53]
Rep
ort
Ora
lT
ET
?o
ral
CS
?to
pic
alC
S9
18
–6
1(m
ean
45
)
12
wee
ks
Yes
No
Res
olv
ed–
[54]
Rep
ort
:O
ral
TE
T?
topic
alH
C(1
5)
:O
ral
TE
T?
topic
ald
eso
nid
e(1
2)
:T
opic
alH
C(6
)/des
onid
e(7
)
40
15
–4
5(m
ean
22
.6)
6–
12
wee
ks
No
No
:O
ral
TE
T?
topic
alH
Cre
solv
edin
\1
2w
eek
s
:O
ral
TE
T?
topic
ald
eso
nid
ere
solv
edin
\1
2w
eek
s
:T
op
ical
s—co
mp
lete
lycl
eare
d
–[5
5]
Rep
ort
Ora
lT
ET
?to
pic
alC
S4
33
2.2
[6
–1
2w
eek
sY
esN
oD
ata
no
tcl
ear
–[5
6]
Rep
ort
To
pic
alT
ET
30
18
–5
94
wee
ks
Yes
No
:8
0%
reso
lved
in5
–2
8d
ays
:H
alf
of
the
lesi
on
sre
solv
edin
10
%o
fp
tsin
28
day
s
:1
0%
dis
con
tin
ued
med
icat
ion
–[5
7]
Rep
ort
Ora
lT
ET
11
6–
[6
wee
ks
Yes
No
Res
olv
edin
[6
wee
ks
Rep
eate
dco
urs
esw
ere
do
ne
for
8p
ts[4
6]
Ser
ies
To
pic
alH
C?
top
ical
ER
Y6
18–33
8w
eeks
Yes
No
Res
olv
edin
2–8
wee
ks
(5w
eeks)
HC
pre
ven
ted
flar
efr
om
rebo
un
din
g[5
8]
Rep
ort
Ora
lT
ET
/ER
Y?
top
ical
HC
87
28
12
wee
ks
Yes
No
Res
olv
edin
8–12
wee
ks
(12
wee
ks)
–[5
9]
Ran
do
miz
ed,
do
uble
-bli
nd
ed,
mult
icen
ter
:T
op
ical
ME
T(5
4)
:O
ral
TE
T(5
4)
10
81
7–
59
(med
ian
35
)
8w
eek
sY
esN
oP
apu
leco
un
t
:T
op
ical
ME
Tre
solv
edin
[8
wee
ks
:O
ral
TE
Tre
solv
edin
4–
8w
eek
s
Sig
nifi
cant
dif
fere
nce
was
det
ecte
db
etw
een
two
gro
ups
[60]
Ser
ies
Var
iou
sto
pic
als
(ME
T,
ER
Y,
HC
)1
49
mon
ths–
6.5
yea
rs8
wee
ks
Yes
No
Res
olv
edin
1–8
wee
ks
(5w
eeks)
Dura
tion
of
rem
issi
on
was
1–
16
mon
ths
afte
rco
mp
leti
on
of
tx
[61]
106 T. Tempark, T. A. Shwayder
Ta
ble
2co
nti
nu
ed
Stu
dy
des
ign
Reg
imen
No
.o
fp
atie
nts
Ag
e(y
)D
ura
tio
no
ftx
Sto
pC
SS
top
cosm
etic
En
dpo
int/
ou
tco
me
Rem
ark
Ref
eren
ces
Ran
do
miz
ed:
To
pic
alE
RY
(33
)
:O
ral
TE
T(3
5)
:O
ral
PL
(31
)
99
31
30
24
3w
eek
sY
esY
esP
apu
leco
un
t
:T
op
ical
ER
Yre
solv
edaf
ter
50
day
s
:O
ral
TE
Tre
solv
edaf
ter
40
day
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
Perioral Dermatitis 107
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
108 T. Tempark, T. A. Shwayder
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)
Perioral Dermatitis 109
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
110 T. Tempark, T. A. Shwayder
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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Age < 8 years Age 8 years
Systemic treatment Topical treatment
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Systemic treatment
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