| |

Received: 6 August 2019    Revised: 20 August 2019    Accepted: 22 August 2019

DOI: 10.1111/odi.13183

REVIEW ARTICLE

Treatment of angular cheilitis: A narrative review and authors’

clinical experience

Marco Cabras1  | Alessio Gambino1,2 | Roberto Broccoletti1 | Giovanni Lodi3  |

1
Paolo G. Arduino

1
Department of Surgical Sciences, Oral
Medicine Section, CIR‐Dental Abstract
School, University of Turin, Turin, Italy Angular cheilitis (AC) is a clinical entity first described in the XIX century, character‐
2
Department of Mechanical and Aerospace
ized by erythema, rhagades, ulcerations, and crusting of one or both lip commissures
Engineering, Politecnico of Turin, Turin, Italy
3
Department of Biomedical, Surgical and
and perilabial skin, responsible of an unpleasant and painful discomfort. Aim of this
Dental Sciences, University of Milan, Milan, manuscript was to examine and evaluate the therapeutic options actually available
Italy
for AC. Despite antifungals being the first‐line treatment for most of clinicians, very
Correspondence limited scientific evidence supports their reliability, with just two RCTs published be‐
Dr. Marco Cabras, Department of Surgical
Sciences, CIR‐Dental School, School of
tween the 70’s and the 80’s. Furthermore, alternative topical treatments, various
Medicine, University of Turin, Oral Medicine techniques of occlusal vertical dimension restoration, B‐vitamin supplementation,
Unit, Via Nizza 230, I‐10126 Turin, Italy.
Email: [email protected]
anti‐drooling prosthetic device, and photodynamic therapy have been experimented
and proposed, mostly in the form of case reports or case series on a small number of
individuals. Our group found in 1% isoconazole nitrate (ISN) and 0.1% diflucortolone
valerate (DFV) ointment the most consistent AC treatment, due to the broad spec‐
trum of ISN against many species of dermatohpytes and bacteria, and the anti‐inflam‐
matory properties displayed by DFV. However, further and well‐designed trials on
larger samples of patients are needed to assess the differential profile of consistency
of the treatments outlined in literature and claimed by the authors of this paper.

KEYWORDS
angular cheilitis, cheilitis, narrative review, outcome, treatment

1 |  I NTRO D U C TI O N skin, either in one commissure or both. This form is downright differ‐
ent from other well‐known possibly dysplastic labial diseases (Pilati,
Angular cheilitis (AC) was first described in 1855 by Dr. Lemaistre Bianco, Vieira, & Modolo, 2017).
(Lemaistre, 1855) with the term “perlèche,” from the French word The most comprehensive categorization of AC clinical spectrum was
“pourlècher” (to lick one's lip), being characterized by aphthous‐like formulated in 1986 by Ohman and co‐workers. Small rhagades limited to
ulcers at the corner of the lips forcing patients, especially children, to the corner lips with slight skin involvement were defined as type I; deeper
“lick their lips at any time.” and more extensive lesions with uneven borders were described as type II;
Today, AC is by far the most common term used in dental and several rhagades extending from the lip corners into the perioral skin were
dermatologic literature, suggesting an inflammation (suffix—itis) at referred as type III. Finally, a diffuse erythema spread in the skin surround‐
the corner (angular) of the lips (Greek term “cheilos”). ing the vermillion border would fall into type IV (Ohman, Dahlén, Möller,
Clinically, it is a frequent condition characterized by erythema, & Ohman, 1986). To date, this classification is still considered reliable and
rhagades, ulcerations, and crusting of the lip corners and the adjacent exhaustive as the most recent case series show (Oza & Doshi, 2017).

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved

Oral Diseases. 2019;00:1–9. wileyonlinelibrary.com/journal/odi |  1

  
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2       CABRAS et al.

The etiology of AC is extremely varied, with many local and/or In light of such an extensive combination of multiple factors,
systemic causes responsible for first onset and recurrence. Clinical we tried to conduct a review of the literature concerning AC ther‐
experience suggests a direct link between insufficient or inappropri‐ apeutic approaches, with the aim of assessing if there is any solid
ate support of the lip corners and AC appearance, through salivary experimental evidence behind the most commonly prescribed
stasis and maceration of the commissures. In this sense, reduced ver‐ treatments.
tical dimension caused by edentulism or ill‐fitting dentures, weight
loss, malnutrition, smoking, and mouth breathing can be recalled as
local causes of AC (Park, Brodell, & Helms, 2011). 2 | M E TH O DS
Among the iatrogenic causes, orthodontic treatment (Cross,
Eide, & Kotinas, 2010; Cross & Short, 2008) and surgical procedures From June 2018 to November 2018, two researchers (PGA and RB)
such as tonsillectomy have been described (England, Lau, & Ell, conducted a review on the treatment of AC. No initial restriction
1999), with nickel‐based braces being potentially responsible for an has been posed concerning the date of publication. Inclusion crite‐
allergic form (Yesudian & Memon, 2003). ria were as follows: case reports, case series, open clinical trials and
Candida albicans, Streptococcus aureus, and Streptococci are randomized controlled trials (RCTs) written in English, conducted
commonly associated with AC, with the former being cultured on human patients, with clinical and/or microbiological features of
since the 1920s (Finnerud, 1929; Ohman et al., 1986; Schoenfeld angular cheilitis, undergoing a specific treatment carried out by den‐
& Schoenfeld, 1977; Schwab & Brasher, 1977; Warnakulasuriya, tist/oral physician/dermatologist.
Samaranayake, & Peiris, 1991): pseudohyphae and budding yeasts Exclusion criteria were applied to articles published in a language
have been detected in 48% (Warnakulasuriya et al., 1991) up to 93% other than English, reviews concerning the treatment of angular
of cases (Schoenfeld & Schoenfeld, 1977). cheilitis, and “non‐inherent” studies, defined as such when:
Concerning the systemic causes, nutritional deficiencies such as
iron, riboflavin, thyamin, and cobalamin deficiencies have been in‐ • not performed on human patients whatsoever;
vestigated since the 1960s (Mäkilä, 1969; Murphy & Bissada, 1979), • describing other forms of microbial or allergic cheilitis;
being still an issue to this day, particularly among children in devel‐ • not mentioning fungal cheilitis in any way;
oping countries, where AC can arise as one of the several signs of • reviewing or describing causes and/or pathogenesis of fungal
malnourishment (Kaur & Goraya, 2018). cheilitis without discussing treatment of such condition;
Similarly, all the systemic causes of xerostomia—Sjögren syn‐ • Reports of allergy or drug‐induced AC, where the mere with‐
drome, diabetes mellitus, radiotherapy of head‐and‐neck district, drawal from the allergen or drug was enough to provide complete
salivary neoplasms, neurological disorders, drugs—must be recol‐ remission of signs and symptoms of AC.
lected in the differential diagnosis (Błochowiak et al., 2016; Skiba‐
Tatarska, Kusa‐Podkańska, Surtel, & Wysokińska‐Miszczuk, 2016). The research was conducted on Google Scholar, as well as the follow‐
Genetic disorders such as Down syndrome may be associated ing electronic databases: Cochrane Library, NIH (National Institute of
with recurrent Candida‐mediated AC (Ercis, Balci, & Atakan, 1996; Health), PubMed, Scopus, Up To Date, Web of Science.
Scully et al., 2002), as well as autoimmune bullous diseases (Caetano The initial search comprised the MeSH terms “Angular Cheilitis
Lde, Enokihara, & Porro, 2015), orofacial granulomatosis (McCartan Treatment” “Angular Cheilitis Therapy.” The complete search strat‐
et al., 2011), and Crohn's disease (Howell, Bussell, Hegarty, & egy used for PubMed electronic database was angular [All Fields]
Zaitoun, 2012) where AC can even occur as the initial sign of the AND ("cheilitis"[MeSH Terms] OR "cheilitis"[All Fields]) AND ("thera‐
underlying disease (Bangsgaard, Weile, & Skov, 2011). py"[Subheading] OR "therapy"[All Fields] OR "treatment"[All Fields]
Some systemic infections, such as secondary syphilis, have been OR "therapeutics"[MeSH Terms] OR "therapeutics"[All Fields]).
correlated with AC, where false forms may arise (Eyer‐Silva et al., Initially, no language restrictions were applied, aiming to exclude
2017), and HIV/AIDS, where differences in the AC flora can be not‐in‐English studies in the first phase of study selection. On the
found between seronegative and seropositive patients (Krishnan & contrary, no restriction regarding the publishing year was carried
Kannan, 2013). out.
Finally, AC may be a side effect of drug assumption. Paroxetine
(Verma, Balhara, & Deshpande, 2012), tetracyclines (McKendrick,
1968), and metronidazole can trigger the condition, being the latter 3 | R E S U LT S
responsible of an unusual association of AC and aphthous‐like ulcers
(Hushan & Bhushan, 2016). Moreover, changes in skin fragility, trig‐ Two reviewers (PGA and RB) independently identified 3,313 articles,
gered by isotretinoin, can lead to AC elicited by Staphylococcus aureus classified as follows: 1,646 duplicates, 1,590 not inherent for the
(Graham, Corey, Califf, & Phillips, 1986). Among biologic agents, it is aim of our work, 65 published in other‐than‐English, 6 case reports,
worth mentioning secukinumab, which can be responsible for per‐ 3 case series, 2 RCTs, 1 open clinical trial. Due to the very limited
sistent forms of AC due to its ability to suppress keratinocyte prolifer‐ amount of evidence available, a narrative description of each treat‐
ation and differentiation (Hitaka, Sawada, Okada, & Nakamura, 2018). ment has been provided.
 CABRAS et al.

TA B L E 1   Available studies for topical treatments of AC

Reference Type of study Size of sample Drug used Main findings

Reiches (1953) Case series 13 patients with AC “silicote” ointment (compounded of 30% silicone oils in a Healing (undefined) after 3–8 days for 8 patients
petrolatum base) containing 3% boric acid or 2% ammoni‐ with no ill‐fitting dentures;
ated mercury “good results” (undefined) for 4 patients with ill‐fit‐
ting dentures;
Recurrence one week after discontinuation for one
patient
Nairn (1975) Randomized 46 pts Group 1:500,000‐U Nystatin tablets 4 times daily for one Group 1:77% cured after one month
single‐blinded Group 1:13 month Group 2:89% cured after one month
control trial Group 2:18 Group 2:10‐mg fungilin lozenges (Amph.B) four times daily Placebo group: 40% cured after one month
Placebo group: 15 for one month, with no dentures Not possible to establish a comparison between
Placebo group: heat‐denatured fungilin lozenges (placebo) Nystatin and Amph.B
four times daily for one month
Ohman et al. (1988) Open/double‐ 8 pts with identical (type 2) AC infected One commissure treated with 100,000 IU/g Nystatin oint‐ Treatment group: 8/8 sites healed after 4 weeks;
blind study by C. albicans ment 4 times daily for one month no growth of C. albicans one week after disap‐
Contralateral commissure treated with placebo 4 times pearing of the lesions
daily for one month Placebo group: 1/8 sites healed after two weeks;
C. albicans detected in each one of the remaining
lesions (7/8)
Cross and Short Small case series 2 pediatric pts with grade 2 AC while Miconazole nitrate 2% 4 times daily for two weeks Complete remission after one session for one
(2008) under fixed orthodontic treatment patient; unresponsiveness to two sessions of
myconazole for the other patient, leading to sus‐
pension of fixed orthodontic treatment
da Cunha Filho et al. Case report 58‐y‐o man with plasma cell AC of the Pimecrolimus twice daily for 90 days Partial improvement, although a complete remis‐
(2014) right commissure, unresponsive to an‐ sion could not be achieved after two years
tibiotic, topical antifungals, infiltration
with triamcinolone, cryosurgery
Kumar et al. (2016) Clinical trial 10 pts with AC—no details regarding Ozonized olive oil applied twice daily Healing reached within 2.3 days—no further details
clinic and/or microbiologic features in terms of follow‐up visits

Abbreviations: AC, angular cheilitis; IU, International Unit; Pts, patients; U, Unit; y‐o: years old.
|
      3
TA B L E 2   Available studies for OVD restoration techniques as treatment of AC
|

Reference Type of study Size of sample Treatment provided Main findings

4      

Symingtn (1971) Case series 8 pts edentulous pts with dentures affected by Surgical excision of the area affected by AC; closure 7 pts displayed postoperatory healing
AC unresponsive to antifungal creams of the surgical defect with rotated, raised vertical 5 showed no recurrence after two years
mucosal flap
In six cases, surgery performed under general
anesthesia
Chernosky (1985) Case report 2 pts with decreased OVD and AC Injection of 2 ½ vials of purified bovine collagen No reoccurrence after 8 months for patient n.1
implant (Zyderm®) nine times in a 6‐month period No reoccurrence after 3 months for patient n.2
for patient n.1
Injection of two vials of purified bovine collagen im‐
plant (Zyderm®) on three occasions over a period
of 2 months for patient n.2
Lorenzo‐Pouso et al. Case report 80‐y‐o patient with recurrent bilateral AC After bilateral intraoral mental nerve block, hyalu‐ Immediate relief with no recurrence of AC in the
(2018) reluctant to prosthodontics treatment ronic acid dermal filler (Surgiderm 30; Inibsa) was next 12 months
injected in both mentolabial sulci with a 28‐gauge
needle

Abbreviations: AC, angular cheilitis; OVD, occlusal vertical dimension; Pts, patients; y‐o, years old.

TA B L E 3   Available studies for alternative treatments of AC

Reference Type of study Size of sample Treatment provided Main findings

Murphy and Case report 25‐y‐o three‐month pregnant woman with iron Two capsules of ferrous sulfate twice daily Disappearance of AC and no recurrence
Bissada (1979) deficiency anemia and AC Duration: six months?
Lu (2007) Case report 87‐y‐o woman with recurrent AC and drooling of Mandibular removable prosthesis, combined with a catheter Ceasing of drooling and no recurrence of
saliva persisting for four years device in the posterior left flange to prevent drooling, and AC
redirect saliva in the oropharynx
Rocha et al. Case report 28‐y‐o man with AC after 19 days of chemotherapy Nystatin 100,000 IU/ml, miconazol gel 2% four times daily, Immediate disappearance of pain right
(2016) with methotrexate for acute lymphoblastic combined with aPDT (application of Methylene Blue after aPDT application
leukemia 0.01% for five minutes, continuous diode laser irradiation, Improvement of wound healing and pain
660 nm, 120 J/cm2, 120 s, 4.8 J, 40 mW, 1 W/cm2, spot size after LLLT (VAS going down to 0 after
0.04 cm2), and LLLT (660 nm, 10 J/cm2, 40 mW, 0.4 J and laser irradiation)
10 s/per point)

Abbreviations: AC, angular cheilitis; aPDT, antimicrobial photodynamic therapy; IU, nit; LLLT, low‐level laser therapy; VAS, Visual Analogue Scale; y‐o, years old.
CABRAS et al.
CABRAS et al. |
      5

The following treatments have been described: topical treat‐ side they were to be used, and instructed to apply both devices four
ments (Table 1), occlusal vertical dimension (OVD) restoration tech‐ times a day. Moreover, patients were urged to wear rubber gloves
niques (Table 2), and other treatments (anti‐drooling prosthetic and to change them between the applications, in order to minimize
rehabilitation, vitamin supplementation, and photodynamic therapy, contamination on each site. With healing defined as a combination
Table 3). of disappearance of signs of inflammation and negative microbial
sampling for C. albicans, nystatin appeared to be significantly more
effective than placebo (p < .001), with all sites treated with the an‐
3.1 | Topical treatments
tifungal device being able to heal completely after four weeks of
treatment, and no growth of C. albicans detected one week after
3.1.1 | Silicone‐based oils
clinical remission. On the other hand, only one of the eight commis‐
Topical application of silicone oils was attempted in the 1950s sures treated with placebo achieved complete healing.
(Reiches, 1953) in a small case series of 13 patients (of which 5 with Despite the significant difference obtained through Fisher's
ill‐fitting dentures, affected by AC not caused by ariboflavinosis); a exact probability test, the main limits of this RCT rely in the very
“silicote” ointment (compounded of 30% silicone oils in a petrolatum limited number of patients admitted to the random approach, which
base), containing 3% boric acid or 2% ammoniated mercury, showed is a consequence of the peculiar eligibility criteria chosen by the au‐
promising results among the eight patients with no prosthetic is‐ thors, with bilateral and clinically identical AC being the sine qua non
sues, and the healing was reached after three to eight days. On the condition required for enrollment in the study.
other hand, four of the five patients with unsuitable dentures had In 2008, a small case series of young patients affected by AC
good results, with one experiencing a recurrence one week after the (Cross & Short, 2008) during orthodontic treatment showed con‐
conclusion of treatment. The main limits of this case series lie on trasting results regarding miconazole nitrate 2% gel when applied
the limited sample of patients enrolled, the lack of details regarding on the affected commissures. Two of the three patients enrolled in
the posology of the ointment as well as for the definition of healing, this study were instructed to apply it four times a day for two weeks,
which appears to be unclear. with one individual achieving complete remission after one session,
while the other was instructed to repeat it twice to no avail, leading
to the interruption of the fixed orthodontic treatment. With just two
3.1.2 | Antifungal agents
patients enrolled and such a split result between them, no univocal
In 1975, a randomized single‐blinded control trial was published evidence can be inferred.
(Nairn, 1975), in which 46 patients with AC and/or denture stoma‐
titis were randomly split into three groups of 13, 18, and 15 indi‐
3.1.3 | Pimecrolimus
viduals. Each patient was blindly treated for one month by sucking
a tablet four times a day containing 500,000 U of nystatin, 10 mg of A unique case of plasma cell angular cheilitis was published in 2014
amphotericin B, or a placebo made of heat‐denatured fungilin loz‐ (da Cunha Filho et al., 2014), with a 58‐year‐old man presenting with
enges, respectively. an asymptomatic, red‐purplish ulcerated plaque in the right commis‐
After one month, 77% (10/13) of patients in the first group and sure, unresponsive to antibiotic and antifungal topical treatments.
89% (16/18) of patients in the second group showed a complete clin‐ An incisional biopsy was carried out, showing a normal epider‐
ical remission, with only 40% (6/15) of healing in the placebo group. midis with a dense dermal infiltrate of lymphocytes, neutrophils and
This study carries some limitations, such as the discrepancy in sample an unusual infiltration of mature plasmocytes. After unsuccessful
size between the 52 patients reported in “Methods” and 46 patients infiltration with triamcinolone and cryosurgery, pimecrolimus topi‐
whose results were described, the smallness of the sample preclud‐ cal cream application twice a day finally lead to an almost complete
ing comparison between nystatin and amphotericin B, lack of details remission, after 90 days of treatment. The main limit of this study
concerning intra‐perioral recurrence found in 16 of 31 patients one lies in its own uniqueness, with no other case of “plasma cell” angular
month after the end of the anti‐mycotic medications. However, this cheilitis reported within this very case report or in literature to rely
trial has the merit of giving, for the first time in literature, evidence on for comparison.
about the role of Candida albicans in the pathogenesis of AC.
In 1988, an open and a double‐blind study on 58 patients with AC
3.1.4 | Ozonized olive oil
was published (Ohman & Jontel, 1988). More in detail, while 50 pa‐
tients were divided into four groups according to the original micro‐ The reliability of ozonized olive oil in treating various oral lesions
bial sampling, either C. albicans, S. aureus or both, and openly treated was tested in a recent clinical trial of 50 patients (Kumar et al., 2016),
either with nystatin, fusidic acid or both, eight patients with bilat‐ of which ten with AC: twice a day topical application was success‐
eral and clinically identical type 2 AC, infected only with C. albicans, ful in each one of these patients, with a mean of 2.3 days to reach
were enrolled in a double‐blind study. Therefore, they were given complete healing. The small size of the sample and the shortage of
two undistinguishable tubes of ointment (nystatin 100,000 IU/g vs. information regarding the clinic and/or microbiologic characteristics
placebo), labeled with a red or green marker, depending on which of AC before treatment are the main limitations of this protocol.
 |
6       CABRAS et al.

3.2 | Occlusal vertical dimension (OVD) 3.3 | Other treatments

restoration techniques
3.3.1 | Vitamin supplementation
3.2.1 | Surgery
Although a large case series of 339 patients (Mäkilä, 1969), of which
A small case series of eight patients was published in 1971, 61 with AC, detected significantly lower values of serum thiamine
(Symingtn, 1971) proposing a surgical correction of AC, as an al‐ (p < .05), free riboflavin (p < .02), and dietary intake of iron in these
ternative for those individuals with chronic and discomforting AC, patients when compared to controls, there is very low evidence con‐
especially if not‐responding to the removal of the local and hema‐ cerning a cause–effect relationship between vitamin supplement
tological abnormalities and application of antifungal creams. The and resolution of AC.
operative procedure, performed under general anesthesia in six In this sense, our research lead to one case report published in
cases, consisted of excision of the affected area, preserving the 1979, where a 25‐year‐old pregnant woman with iron deficiency
underlying muscle coat, followed by the delineation of a vertical anemia and AC was successfully treated with two capsules twice a
mucosal flap, which was then rotated, raised, turned into the initial day of ferrous sulfate (Murphy & Bissada, 1979). The study design
defect and sutured. An additional suture was performed to close and the lack of information regarding duration of treatment repre‐
the vertical defect by direct approximation of the edges. Such tech‐ sent the main limitations; to our knowledge, no other case of AC
nique displayed encouraging results, with seven patients exhibiting strictly related to iron deficiency anemia has been reported.
postoperatory healing and five individuals with no recurrence after
two years. The main limit of this study lies in the operator depend‐
3.3.2 | Anti‐drooling prosthetic rehabilitation
ency of such technique, which also required hospitalization of 75%
of these patients, as well as the small number of patients enrolled. A case report of exclusively prosthodontic management for persist‐
Moreover, surgery for a recurrent microbiological condition should ing AC and salivary drooling in an 87‐year‐old woman was described
not be proposed, differently from other labial conditions (Carvalho (Lu, 2007). A mandibular removable prosthesis was forged, with oc‐
et al., 2019). clusal splints of various thicknesses tested in order to restore an ap‐
propriate and comfortable vertical dimension of occlusion. However,
since this alone was not sufficient to eradicate drooling, a catheter
3.2.2 | Collagen implants
device was carved within the left flange in order to pool the saliva
In the 1980s, (Chernosky, 1985) injection of collagen implants was in the oropharyngeal area, thus facilitating swallowing. With this ad‐
pursued in two patients with a decreased vertical facial dimen‐ ditional device, drooling ended and AC did not recur. The anecdotal
sion. Purified bovine collagen implant (Zyderm®) was injected in the nature of evidence, with no follow‐up available, and the high pros‐
depths of the commissures, with no recurrences in the subsequent thodontic expertize required to carry out such a tailored rehabilita‐
three and eight months of follow‐up. The main limit of the paper tion represent the main limits of this report.
resides in the sheer scarcity of patients involved, with no further
studies by the same authors or others experimenting again with this
3.3.3 | Photodynamic therapy
protocol.
In 2016, (Rocha, Melo Filho, & Simões, 2016) a case report described
the treatment with photodynamic therapy (aPDT) in a 28‐year‐old
3.2.3 | Hyaluronic acid dermal fillers
diagnosed with acute lymphoblastic leukemia suffering from AC at
A case report of an 80‐year‐old patient with recurrent bilateral the right commissure. After the application of Methylene Blue 0.01%
AC unresponsive to topical anti‐mycotics was described in 2018 for 5 min, aPDT was performed with a continuous diode laser irra‐
(Lorenzo‐Pouso, García‐García, & Pérez‐Sayáns, 2018). In this diation, 660 nm, with a dose of 120 J/cm2, 120 s (one point), 4.8 J,
case, due to the reluctance of the patient to undergo prosthodon‐ 40 mW, 1 W/cm2, and spot size 0.04 cm2, leading to an immediate
tics treatment, a non‐surgical facial aesthetics (NSFA) technique pain relief and re‐epithelization of the site. The study design itself,
was proposed. After bilateral intraoral mental nerve block, hyalu‐ with only one patient enrolled in this protocol, and the cost‐effec‐
ronic acid dermal filler (Surgiderm 30; Inibsa) was injected in both tiveness of aPDT represent its main limits.
mentolabial sulci with a 28‐gauge needle. The patient experienced
an immediate relief with no recurrence of AC in the following
12 months. As emphasized by the authors, the main limitations 4 | D I S CU S S I O N
of this approach consist in the accuracy of patients’ enrollment,
due to the absolute and relative contraindication related to NSFA Bearing in mind the complexity of AC etiopathogenesis, aim of the
techniques, as well as the high level of training required by the oral present report was to provide a narrative description of the treat‐
physician. ments available for AC.
CABRAS et al. |
      7

With only two RCTs available, both published before the 1990s On the other hand, in vitro evidence showed antibacterial ac‐
(Nairn, 1975; Ohman & Jontel, 1988), it seems appropriate to state tivity of ISN against Staphylococcus aureus, Staphylococcus haemo-
that, to date, there are no sufficient data to establish which treat‐ lyticus, up to methicillin‐resistant Staphylococcus aureus through
ment is more reliable in managing AC in the everyday clinical practice. the production of reactive species of oxygen (ROS), and specifi‐
Moreover, all of the aforementioned therapeutic alternatives to cally singlet oxygen, thus triggering apoptosis (Czaika, Siebenbrock,
antifungals throughout the last six decades cannot be considered Czekalla, Zuberbier, & Sieber, 2013).
reliable, being discussed in either isolated case reports, small case When combining ISN with a topical corticosteroid, such as
series or open trials, with samples ranging between eight and 20 diflucortolone valerate (DFV), further benefits can occur: apart
patients. from the immediate relief from symptoms mediated by inflamma‐
In our everyday clinical practice, vitamin deficiency is rarely the tion, such as itching and erythema, vasoconstriction caused by
main cause of AC; furthermore, whenever a vitamin deficiency is DFV might lead to an enhanced concentration of ISN in the muco‐
present as an underlying condition, AC is not the only oral pathol‐ cutaneous site. Furthermore, the corticosteroid itself can reduce
ogy that can be encountered. Usually, a more comprehensive pattern the symptoms of hypersensitivity from the antifungal itself ignited
arises, inclusive of tongue atrophy, candidiasis, aphthous‐like ulcers, by the release of fungal toxins (Havlickova & Friedrich, 2008). A
and burning sensation or sore mouth. Therefore, vitamin supplements review on the clinical application and safety of 1% ISN plus 0.1%
alone seem not to be an appropriate therapy for most cases of AC. DFV for dermatomycoses underlines the triple‐action profile
Similarly, surgical approaches or silicone‐based oils should not be based on the data from four decades of clinical experience and
considered a first line of treatment: the former, due to the sheer im‐ various clinical trials, and the remarkable profile of safety, with
balance between risks, such as the necessity of general anesthesia, only 19 medically confirmed adverse drug reaction case reports
and potential benefits; the latter, due to the more promising efficacy recorded in more than twenty years of postmarketing surveillance
of ointment or oils exhibiting antibacterial and antifungal properties. (Veraldi, 2013).
Photodynamic therapy and NSFA seem to be highly limited ap‐ In light of the limited evidence available in literature for alterna‐
proaches, since both demand detailed understanding and intensive tive treatments, our group is committed in conducting randomized
training, which are not going to be achieved by the vast majority of clinical trials involving the 1% ISN and 0.1% DFV ointment as exper‐
general practitioners, nor are they required in the everyday clinical imental treatment for patients with AC, in order to assess if such a
practice. solid consistency in the dermatological field can be also reproduced
Moreover, pimecrolimus, as an immunosuppressor, should be and observed on perioral and intraoral lesions.
reserved only in case of an AC unresponsive to antibiotics and anti‐ Further and larger randomized controlled studies are in fact
fungals, in which the inflammatory nature is confirmed through bi‐ needed to shed light on the true weight of an anti‐mycotic therapy in
opsy, in order to avoid a paradoxical worsening of clinical signs and the management of AC, either alone or combined with topical corti‐
symptoms. costeroid, with particular attention needed for chronic and recurrent
In absence of robust evidence from literature, the authors still AC, which seem to hide a multifactorial etiopathogenesis.
rely on their clinical experience: it is authors’ personal opinion that The present review shows lack of evidence regarding AC ther‐
the topical treatment with antifungals combined with corticoste‐ apy, despite its frequent prevalence in the population, especially
roids is the most reliable therapeutic option against AC, combined among the elderly. Further studies are needed to assess if novel
with denture relining, if needed. therapeutic approaches may replace the anti‐mycotic formula‐
More specifically, during the last ten years of clinical practice, our tion, which, despite the scarcity of evidence, are by far the most
group found in a specific ointment (e.g., 1% isoconazole nitrate and frequently prescribed. An appropriate evaluation of the patient's
0.1% diflucortolone valerate) the utmost consistency in providing a general health and a thorough investigation of the underlying local
speedy recovery from AC, with a posology of two applications per factors are essential, since its underestimation might contribute
day for two weeks. Isoconazole nitrate (ISN) has been used success‐ not only to the onset but also, and more importantly, to the recur‐
fully in the treatment of dermatomycoses (Havlickova & Friedrich, rence of AC.
2008; Veraldi, 2013), a well‐known clinical entity among dermatol‐
ogists, which shares part of the microbial and fungal etiology at‐
C O N FL I C T S O F I N T E R E S T
tributed to AC, being triggered by dermatophytes and frequently
superinfected by bacteria of Staphylococcus species. ISN alone None.
seems to exhibit a broad spectrum against many species of dermato‐
phytes (Yang, Wiederhold, & Williams, 2008), such as Microsporum
AU T H O R C O N T R I B U T I O N
spp., Trichophyton spp., Epidermophyton spp., and yeasts, such as
Candida albicans, Candida parapsilois, Candida kruzei (Havlickova & All the authors were involved in the design of the study. PGA and RB
Friedrich, 2008), through reduction of adenosine triphosphate (ATP) conducted the database searches and drafted the paper. PGA, MC,
(Odds, Cheesman, & Abbott, 1985) and inhibition of synthesis of er‐ and GL analyzed the data. All of the authors were involved in writing
gosterol (Fromtling, 1988). the manuscript.
 |
8       CABRAS et al.

ORCID Hushan, A., & Bhushan, S. T. V. (2016). Metronidazole induced aphthous

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Kaur, S., & Goraya, J. S. (2018) Dermatologic findings of vitamin B12 de‐
Giovanni Lodi  https://orcid.org/0000-0002-0218-8292
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