Classification Immunopathogenesis Underlying Conditions & Etiology Clinical Features Diagnosis Management Conclusions

Recurrent Aphthous Stomatitis
Introduction
Classification
Immunopathogenesis
Underlying Conditions & Etiology
Attilio Boner
Clinical features
University of Diagnosis
Verona, Italy
attilio.boner@univr.it Management
Conclusions
•Recurrent aphthous stomatitis (RAS) is the most common

inflammatory and ulcerative condition of the oral cavity.
•The term aphthous is derived from a Greek word aphtha,

which means ulceration.
•It is estimated that at least 1 in 5 individuals

have been affected by aphthous stomatitis.
•The disorder most commonly affects young adults

(with some studies reporting a prevalence as high as 60% in students),
decreasing in frequency and severity after 50 years of age.
Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

1) underlying infectious,
The cause is unknown in most
2) inflammatory,
patients, although in some the
disease manifests secondary to:
3) immunologic,
4) nutritional disorder,
5) genetic diseases.

Introduction
Classification
Attilio Boner
Verona, Italy
Conclusions
Recurrent Aphthous Stomatitis : Classification
Recurrent aphthous
stomatitis has
2 presentation forms
and 3 morphological
types.
The 2 forms are

simple and complex
aphthosis,
and the
3 morphological types
are:
minor, major and
herpetiform aphthous
ulcers.
Baccaglini L. Oral Dis.
2011;17:755e770.
Recurrent
Complexaphthous
aphthosis
stomatitis
refershasto the
persistent
and 3 morphological
types. presence of
≥ 3 ulcers,
Theassociated
2 forms aregenital
simple lesions, and
and complex
resultant serious
aphthosis,
and thedisability,
3 morphological types
in the absence
are:
of Behçet disease.
minor, major and
herpetiform
Keogan MT. aphthous
Clin Exp
ulcers. Immunol.
2009;156:1e11.
2011;17:755e770.
Ocular lesions
Recurrent (uveitis),
aphthous
stomatitis
erythemahas nodosum,
pustular lesions,
and 3 morphological
cutaneous pathergy
types.
(nodule formation after
intradermal
The 2 forms are injection
simpleof
andsaline),
complexand
aphthosis,
bizarre neurologic
and the
3 findings alsotypes
morphological occur in
Behcet Disease, setting
are:
thismajor
minor, condition
and apart.
herpetiform aphthous
ulcers.
Mat MC. Clin Dermatol.
2014;32:435e442.
2011;17:755e770.
Morphological Types
RAS has been classified
based on the 1. minor aphthae
(Mikulicz aphthae),
size and evolution
of lesions
into 3 types: 2. major aphthae
(Sutton disease, also
referred to as
The superficial lesions are periadenitis mucosa
rounded, with a yellow-colored necrotica recurrens),
slough (pantano) and surrounding
erythema, and may result 3. herpetiform ulcerations.
in scarring and, rarely,
tissue destruction.

Table 1: Classification of Recurrent Aphthous Stomatitis (RAS)

Clinical Immunology Review Series: an approach to the
patient with recurrent orogenital ulceration, including
Behçet’s syndrome. Keogan MT. Clin Exp Immunol. 2009;156:1e11.
complex aphthosis,
Behçet's disease,
Patients presenting with secondary complex aphthosis
recurrent orogenital ulcers (e.g. Reiter's syndrome, Crohn's disease,
may have cyclical neutropenia) or
non-aphthous disease (including bullous disorders,
erythema multiforme, erosive lichen planus).
Behçet's syndrome is a multi-system vasculitis of unknown aetiology

for which there is no diagnostic test.
Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and
2 of the following:
•recurrent genital ulcers,
•ocular inflammation,
•defined skin lesions (erythema nodosum, papulo-pustular lesions)
•pathergy.
Clinical Immunology Review Series: an approach to the
patient with recurrent orogenital ulceration, including
Behçet’s syndrome. Keogan MT. Clin Exp Immunol. 2009;156:1e11.
Pathergy describes
cutaneous
hyperresponsiveness to
trauma which, when elicited
correctly, is quite specific
for Behcet’s Disease.
After skin-cleansing with

alcohol swabs, two or more
large (20 G) needles are
inserted subcutaneously
(minimum depth 3 mm),
a few centimetres apart,
(+) (-)
and read at 48 h.
Development of a papule or pustule at the site of insertion

is considered positive, while erythema or a residual
pin-prick mark is negative.
Introduction
Classification
Attilio Boner Clinical features
University of
Verona, Italy
Diagnosis
attilio.boner@univr.it
Management
Conclusions
Recurrent Aphthous Stomatitis: Pathogenesis
•The pathogenesis of aphthous stomatitis is largely unknown, although an

abnormal T-cell-mediated immune reaction appears to be involved in patients
with RAS.
•IFN-γ, IL-2, IL-4, IL-5, but not for IL-10,

lesion are suggesting defective tissue healing responses.
infiltrated •tumor necrosis factor a (TNF-a) and
•interleukin 15 (IL-15),
•TH2-related genes are not overexpressed in RAS tissues.

X
•A role for oral microbiota in disease pathogenesis
also been proposed. Bankvall M. J Oral Microbiol. 2014;6:25739.

Introduction
Classification
Attilio Boner Clinical features
University of
Verona, Italy
Diagnosis
attilio.boner@univr.it
Management
Conclusions
Recurrent Aphthous Stomatitis:
predisposing factors
•Although most patients with RAS have a primary form of the disease,
certain inflammatory, nutritional, toxic, and metabolic factors
may contribute to disease pathogenesis.
•Predisposing factors for aphthous stomatitis include:

trauma;
tobacco use;
use of certain medications;
deficiencies of vitamin B12, iron, zinc, and
folic acid;
gluten sensitivity (and enteropathy);
chemical irritants, including sodium lauryl sulfate
(found in certain brands of toothpaste);
hormonal changes; and
microbial factors
Recurrent Aphthous Stomatitis: underlying conditions
Conditions
associated with
complex aphthae
that may be seen
by an allergist
immunologist.
CBC, complete blood cell

count;
CRP, C-reactive protein;
ESR, erythrocyte
sedimentation rate;
MAGIC, Mouth and genital
ulcers, inflamed cartilage;
PFAPA, periodic fever,
aphthous stomatitis,
pharyngitis, adenopathy.
Shah K,
Ann Allergy
Asthma Immunol.
2016;117(4):341-343
Recurrent Aphthous Stomatitis: underlying conditions
Conditions
associated with
complex aphthae
that may be seen
by an allergist
immunologist.
CBC, complete blood cell simple aphthosis

count;
CRP, C-reactive protein;
may be associated with celiac disease
ESR, erythrocyte and gluten sensitivity
sedimentation rate;
MAGIC, Mouth and genital
ulcers, inflamed cartilage;
PFAPA, periodic fever,
aphthous stomatitis,
pharyngitis, adenopathy.
Shah K,
Ann Allergy
Asthma Immunol.
2016;117(4):341-343
Recurrent aphthous stomatitis as a marker of celiac
disease in children. Marty M, Pediatr Dermatol. 2016;33:241.
•In children, the association of symmetric enamel

defects with recurrent oral ulcerations has been
considered a presentation of silent celiac disease.
+
•Thus, children with a documented history of RAS
should undergo a dental examination and, if
positive, be referred to a gastroenterologist
who will conﬁrm the diagnosis.
≈
Is RAS associated with Celiac Disease?
Baccaglini L. Oral Dis. 2011;17:755-770.
Celiac disease (CD)
The
prevalence
of CD in
pateints with
RAS
has been
reported
between
4% and 40%
of cases
Celiac disease (CD)
the number of CD patients

who have RAS ranges from
3–61%
compared against an approximately
37% lifetime prevalence of RAS
in the general population
Celiac disease (CD)
•In some cases, oral ulcers can be the first sign of CD.
•Most of the studies reporting associations between RAS and CD did not
report any well-defined criteria for RAS diagnosis, while the
diagnosis of CD was usually well-supported by biopsy and/or antibody tests.
•Thus, the literature reviewed does support an association between

oral ulcers and CD; however, these oral ulcers may not be RAS.
•The oral ulcers that are a manifestation of CD would respond

to a gluten-free diet, while classical RAS would not.
Is RAS associated with Vitamin B12 deficiency?
Vitamin B12 deficiency
studies indicate that

0–42% of RAS patients
may have a
vitamin B12 deficiency
This variation may be

attributable to
geographical and
temporal variations
in diet and food
supplementation.
Is RAS associated with Vitamin B12 deficiency?
Vitamin B12 deficiency
•Case reports indicate that some cases of RAS in patients with

vitamin B12 deficiency are successfully treated with vitamin B12
supplementation.
•Treatment with vitamin B12 may be of benefit

even in the absence of vitamin B12 deficiency.
although RAS may only rarely be associated with low blood levels
of vitamin B12; treatment with vitamin B12 may nevertheless be
of benefit in RAS, via mechanisms that warrant further study.
Effectiveness of vitamin B12 in treating recurrent
aphthous stomatitis: a randomized, double-blind,
placebo-controlled trial.
Volkov I, J Am Board Fam Med. 2009;22:9–16.
% patients free of ulceration
after 6 months of treatment
58 patients 80 –
suffering from RAS: 70 –
74.1%
60 –
•31 a sublingual dose
of 1000 mcg
50 – p <0.01
40 –
of vitamin B(12),
30 –
32%
•27 placebo 20 –
for 6 months 10 –
00
vitamin B12 placebo
Effectiveness of vitamin B12 in treating recurrent
aphthous stomatitis: a randomized, double-blind,
placebo-controlled trial.
Volkov I, J Am Board Fam Med. 2009;22:9–16.
% patients free of ulceration
after 6 months of treatment
58 patients 80 –
This
suffering significant
from RAS:
response to
70 –
74.1%
60 –
vitamindose
•31 a sublingual B12
of 1000 mcgindependent
was
50 – p <0.01
40 –
of vitamin B(12),
of initial
blood B12 level.
30 –
32%
•27 placebo 20 –
for 6 months 10 –
00
vitamin B12 placebo
Is Periodic Fever, aphthous stomatitis, pharyngitis, and
cervical adenitis (PFAPA) syndrome a distinct medical
entity? Baccaglini L. Oral Dis. 2011;17:755-770.
•First described in 1987, PFAPA syndrome is a clinical entity characterized

by recurrent episodes of fevers without an identifiable source of infection.
Marshall GS, PFAPA syndrome. Pediatr Infect Dis J. 1989 Sep;8(9):658-9.
•The diagnosis is established on the basis of clinical criteria that require the
presence of:
1) a recurrent fever of early onset (<5 years) with a clockwork periodicity

(usual interval <4 weeks) and
2) ≥1 of the 3 associated symptoms:
i) aphthosis, in the absence of upper respiratory

ii) cervical adenitis, tract infections and cyclic neutropenia.
iii) pharyngitis,
•First described in 1987, PFAPA syndrome is a clinical entity characterized

by recurrent The
episodes of fevers
primary withoutisanthe
complaint identifiable
periodicsource
fever of infection.
Marshall GS, PFAPA syndrome. Pediatr Infect Dis J. 1989 Sep;8(9):658-9.
rather than the stomatitis.
•The diagnosis is established on the basis of clinical criteria that require the
presence of:
1) a recurrent fever of early onset (<5 years) with a clockwork periodicity

(usual interval <4 weeks) and
2) ≥1 of the 3 associated symptoms:
i) aphthosis, in the absence of upper respiratory

ii) cervical adenitis, tract infections and cyclic neutropenia.
iii) pharyngitis,
Different cohorts
of patients with
PFAPA
Distribution of
main clinical
manifestations
associated with
fever episodes
While fever is always

present the presence of
aphthae sometimes
is reported in
a minority of the cases.
•Intraoral ulcers in PFAPA are generally described

as few to several, non-clustered, small (<5 mm),
shallow ulcers that heal over 5 to 10 days.
•By definition, the diagnosis of PFAPA syndrome requires also exclusion

of other monogenic periodic fevers, which are hereditary conditions and
include Familial Mediterranean Fever (FMF), the spectrum of mevalonate
kinase deficiencies (MKD) (such as Hyper Ig-D syndrome and mevalonate
aciduria), and tumor necrosis factor-associated periodic
syndrome (TRAPS) amongst others, each characterized
by a specific genetic mutation.
Scully C, Oral Dis. 2008;14(8):690-9.
•A relevant number of patients with monogenic periodic fevers also meet
the diagnostic criteria for PFAPA syndrome.
In a preliminary experience, 83% of patients with mevalonate kinase

deficiency (MKD), 57% of patients with (tumor necrosis factor receptor–
associated periodic fever syndrome (TRAPS), and 8% of patients with
Familial Mediterranean fever (FMF) satisfied the criteria for PFAPA
syndrome, which shows that the criteria have limited utility in
differentiating PFAPA syndrome from monogenic periodic fevers.
•Importantly, although oral aphthosis was found less frequently in monogenic

periodic fever than in PFAPA there was a high overlap with the other signs
and symptoms.
Gattorno M. Arthritis Rheum. 2008;58(6):1823-32.
Gattorno M, Pediatrics. 2009;124(4):e721-8.
A diagnostic score for molecular analysis of hereditary
autoinflammatory syndromes with periodic fever
in children. Gattorno M. Arthritis Rheum. 2008;58(6):1823-32.
OR for a (+) genetic test

40 –
A total of 228
30 –
33.1
consecutive 20 – P < 0.001
patients with a 10 –
clinical history
of periodic fever
4.6
4.0 –
screened for 4.1
mutations in the
3.0 –
P = 0.039 P = 0.05
3.3
MVK, 2.0 – P = 0.028
TNFRSF1A, and P = 0.007
1.0 –
MEFV genes.
0.0
0.2
(+) FH of thoracic abdominal diarrhea oral
periodic pain pain aphthosis
fever
Patients were classified as high risk if their diagnostic score was 1.32;
otherwise, they were classified as low risk.
*age of onset in months (the greater the age of onset the lower the score)
Proposed diagnostic
flow chart for use
in children with
periodic or
recurrent fever.
This score identified

91% of the
genetically positive
individuals
and those at risk for
carrying genes
associated with
monogenic periodic
fevers.
Differentiating PFAPA syndrome from monogenic periodic
fevers. Gattorno M, Pediatrics. 2009;124(4):e721-8.
•In our study, 52% of children (43 of 82 children) with recurrent fever
attributable to monogenic autoinflammatory diseases exhibited positive
results for PFAPA syndrome criteria.
•The proportion was greater for MKD (33 of 40 children) than for FMF
(7 of 30 children) or TRAPS (3 of 12 children).
•We found that some of the features that are considered characteristic
of PFAPA syndrome, such as clockwork-like recurrence of febrile episodes,
oral aphthosis, and enlargement of cervical lymph nodes, are present with
similar frequencies in MKD and also may be present in some genetically
proven pediatric FMF cases.
Differentiating PFAPA syndrome from monogenic periodic
fevers. Gattorno M, Pediatrics. 2009;124(4):e721-8.
•Therefore, because PFAPA syndrome is far more prevalent than the

aforementioned inherited periodic fevers, it is crucial to identify, among
patients with a PFAPA syndrome phenotype, those with higher probabilities
of carrying mutations in genes associated with periodic fever.
•Our findings show that PFAPA syndrome criteria alone are not able to
distinguish genetically positive from genetically negative patients.
•We propose the use of the Gaslini diagnostic score for all patients with
a PFAPA syndrome phenotype. Patients with low risk (score < 1.32) of
carrying relevant mutations may be diagnosed as having PFAPA syndrome
without the need for formal exclusion of inherited periodic fever through
molecular analysis or other clinical or laboratory investigations.
•Conversely, patients with high risk (score > 1.32) should be screened.
Potential use of procalcitonin concentrations
as a diagnostic marker of the PFAPA syndrome.
Yoshihara T, Eur J Pediatr. 2007;166(6):621-2.
serum procalcitonin concentrations
6 PFAPA syndrome patients

(median age of 7.5 yrs)
32 controls
(bacterial n=10, non-bacterial, n=22)
Sampling on the 3rd-5th day of fever.

Potential use of procalcitonin concentrations
as a diagnostic marker of the PFAPA syndrome.
Yoshihara T, Eur J Pediatr. 2007;166(6):621-2.
During febrile episodes in PFAPA

patients, leukocyte counts and
serum procalcitonin concentrations serum concentrations of CRP were
invariably and significantly elevated
to a median of 11,200/μl
6 PFAPA syndrome patients (range 9,600–18,800/μl)
(median age of 7.5 yrs) and 7.9 mg/dl (range 5.7–14.7 mg/dl),
respectively.
an association of high serum CRP with
32ancontrols
elevated leukocyte count and
(bacterial n=10, levels
undetectable non-bacterial, n=22)
of procalcitonin
may be used as a criterion
on the
to distinguish
Sampling an 3inflammatory
rd-5th day of attack
fever.
due to PFAPA syndrome from
an intercurrent bacterial infection.
•In conclusion, it seems that the question that needs to be addressed

is not “Is PFAPA syndrome a distinct medical entity?”,
but rather,
“How to differentiate PFAPA from other similar diseases causing

recurring fever?”.
•In that regard, the importance of oral aphthous ulcers in PFAPA is still
questionable and further specific studies are clearly warranted to better
describe oral ulcerations in PFAPA patients and at large to set up specific
and reliable diagnostic criteria.
Recurrent Aphthous Stomatitis: Etiology
•Infections with human immunodeficiency virus, Yersinia, tuberculosis, and

salmonella have been associated with RAS by some investigators.
•Antibiotics, β-blockers, angiotensin-converting enzyme inhibitors, and

certain antiarrhythmic drugs and non-steroidal anti-inflammatory agents
have been associated with oral ulceration.
Munoz-Corcuera M, Clin Exp Dermatol. 2009;34:456e461.
•Multivariate paired analysis has revealed a significant association between

nonsteroidal anti-inflammatory agent and β-blocker use and aphthous
stomatitis. Boulinguez S, Br J Dermatol. 2000;143:1261e1265.
•Drug-induced ulcers are located usually on the side of the tongue,

are solitary, and are resistant to usual treatments until use
of the medication is discontinued.

Introduction
Classification
Attilio Boner
Verona, Italy
Conclusions
Recurrent Aphthous Stomatitis: clinical features
Aphthous stomatitis presents as shallow, round to oval,

clearly defined, painful ulcers in the oral mucosa.
There are 3 different clinical variants of RAS:
1) minor aphthous stomatitis (Mikulicz aphthae), These ulcers are

relatively
small and shallow.
2) major aphthous stomatitis Notice the

(Sutton disease or significant
difference in
periadenitis mucosa necrotica recurrens), or depth and
irregular shape
of a major ulcer
in comparison to
a minor ulcer.
3) herpetiform ulceration.

(D) A solitary large soft palatal (E) Duodenal biopsy in a patient with celiac disease
ulcer in a patient with demonstrating typical findings including loss of villi
celiac disease. and intense inflammatory cell infiltration.

Introduction
Classification
Attilio Boner
Verona, Italy
Conclusions
Recurrent Aphthous Stomatitis: Diagnosis
•Diagnosis of aphthous
stomatitis can be made by
history, clinical examination, and
histopathologic analysis.
•Diagnostic testing is suggested

in Table 2 and should be based
on history and clinical findings.

Recurrent Aphthous Stomatitis: Diagnosis
•Biopsy of the ulcer is rarely necessary but may be helpful when infection,
vasculitis, or neoplasia cannot be excluded by other means.
•Histopathologic analysis of an aphthous ulcer reveals superficial tissue

necrosis, infiltration by neutrophils, and the presence of cellular debris.
•There is fibrinopurulent exudate, and numerous red blood cells may coalesce
to form hemorrhagic foci.
•The epithelium is infiltrated with variable numbers

of intraepithelial lymphocytes and some neutrophils.
•None of these findings are specific to any disease entity but may help
exclude vasculitis or infection.

Introduction
Classification
Attilio Boner
Verona, Italy
Conclusions
Recurrent Aphthous Stomatitis: Management
•There is no definite treatment for RAS.
•Systemic disorders that underlie RAS need to be evaluated for

and managed effectively.
•Deficiencies of zinc, folate, iron, and/or vitamins B1, B6, and B12
may need to be corrected.
•Underlying inflammatory bowel disease, celiac disease, MAGIC syndrome,

PFAPA syndrome, cyclical neutropenia, Behçet syndrome, Sweet syndrome,
Reiter syndrome, and reactive arthritides or infection may require targeted
therapy, including immunosuppression or the use of biological agents.
Messadi DV, Dermatol Ther. 2010;23:281e290.
Keogan MT. Clin Exp Immunol. 2009;156:1e11.
Baccaglini L, Oral Dis. 2011;17:755e770.
Lankarani KB, World J Gastroenterol. 2013;19:8571e8579.

Education
•Educational and preventive aspects are essential to successful

management of RAS.
•Avoidance of food triggers, especially alcohol, carbonated beverages,

spicy foods (pepper, curry), and acidic fruits (citrus fruits, tomatoes, and
strawberries), may be important. Altenburg A, Dtsch Arztebl Int. 2014;111:665e673.
•Avoidance of oral hygiene products that contain sodium lauryl sulfate

may also be helpful in some patients.
•Oral hygiene is essential and needs to be stressed because poor oral hygiene
might introduce a microbial and infectious component to recurrence or
persistence.

Topical Therapy
•Topical therapies are usually safe, well tolerated, and effective.
•Topical agents can be administered using vehicles such as

oral pain reliever anesthetic paste (Orabase).
•Triamcinolone acetonide, fluocinonide, and

topical anesthetic agents can be applied using
anesthetic paste, up to 4 times a day until healing occurs.
•Patients can be educated to self-treat themselves when a flare occurs

because early treatment might lessen the duration and severity
of the illness.

Topical Therapy
•Topical or minocycline (Minocin ® unguento) has been used with varying success
and might work by antibacterial effects and broader effects on inflammation
and expression of collagenases. Zur E. Int J Pharm Compd. 2012;16:462e469.
•Other interventions include surgical or laser ablation, ultrasonography,

and chemical cautery with silver nitrate and can lead to rapid improvement in
pain, although these modalities have not convincingly accelerated healing.
•Medicated toothpaste that contains the enzymes amyloglucosidase

and glucose oxidase have also been used as adjuncts to chemical cautery.
•The application of topical local anesthetics before cautery

may decrease pain and discomfort.
Immune Modulation
•Oral and intravenous steroids can be used in acute exacerbation

in combination with other immunosuppressants, especially for
complex aphthae or severe disease that results in odynophagia
or intractable pain.
•Thalidomide has significant benefit, especially in patients with

human immunodeficiency virus.
It acts by reducing activity of TNF-a by degrading messenger RNA.
•Pentoxifylline has benefit and probably works by inhibiting

TNF-a production.

Immune Modulation
•Colchicine, levamisole, dapsone, antimetabolites (azathioprine and

methotrexate), biologics (infliximab and etanercept), alkylating
agents (chlorambucil and cyclophosphamide), and interferon alfa
have some benefit in patients with RAS.
Sand FL, J Dermatolog Treat. 2013;24:444e446.
Hasan A, Clin Mol Allergy. 2013;11:6.
•These options can be considered in refractory or disabling RAS, realizing

that the data supporting their use are limited to case studies.
Opportunistic infections and/or late neoplastic complications limit the use of
these medications for minor aphthae..

Are there any new RAS treatments?
•Low dose synthetic tetracyclines (doxycycline and minocycline), particularly

as gel or rinse, appeared to reduce RAS pain and duration, possibly through
local inhibition of collagenases or immunomodulatory effects.
•However, long-term adverse events (AE) are unknown and may include
bacterial resistance, fungal overgrowth and fetal harm.
•Amlexanox, an antiinflammatory drug, showed some

effectiveness short-term, particularly when used during
the prodromal phase.
•Lasers or chemical cauterization may provide fairly rapid pain relief,

attributed to disruption of local nerve endings
or reduction in inflammatory mediators.
•Low dose synthetic tetracyclines (doxycycline and minocycline), particularly

as gel or rinse, appeared to reduce RAS pain and duration, possibly through
local inhibition of collagenases or immunomodulatory effects.
•However, long-term adverse events (AE) are unknown and may include
bacterial resistance, fungal overgrowth and fetal harm.
•Amlexanox, an antiinflammatory drug, showed some

effectiveness short-term, particularly when used during
the prodromal phase.
However, some of these therapies require
repeated
•Lasers or chemical dental
cauterization visits,
may which
provide fairlyare not
rapid pain relief,
feasible of
attributed to disruption long-term
local nerveorendings
for frequent RAS.
or reduction in inflammatory mediators.
•Triamcinolone acetonide in Orabase was used in three trials

as the active control and was less effective than Nd:YAG laser
(for immediate pain relief) or dexamucobase (for accelerating healing).
•Local and topical treatments in general carry lower risks of systemic adverse
effects and should be considered as the first line of treatment.
•Until RAS etiology is discovered, treatment options will remain few and only
partially effective.
Introduction
Classification
Attilio Boner
Verona, Italy
Conclusions
Urban legends: recurrent aphthous stomatitis.
•Recurrent aphthous stomatitis (RAS)

is the most common idiopathic intraoral
ulcerative disease.
•Aphthae typically occur in apparently healthy individuals,

although an association with certain systemic diseases
has been reported.
•Despite the unclear etiopathogenesis, new drug trials

are continuously conducted in an attempt to reduce pain
and dysfunction.
Urban legends: recurrent aphthous stomatitis.
Results from extensive literature searches, including a systematic review of

RAS trials, suggested the following:
(1) Complex aphthosis is not a mild form of Behçet disease;
(2) Diagnostic criteria for PFAPA have low specificity and the
characteristics of the oral ulcers warrant further studies;
(3) Oral ulcers may be associated with CD;

however, these ulcers may not be RAS;
(4) RAS is rarely associated with B12 deficiency; nevertheless, B12

treatment may be beneficial, via mechanisms that warrant further study.

Classification Immunopathogenesis Underlying Conditions & Etiology Clinical Features Diagnosis Management Conclusions

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Classification Immunopathogenesis Underlying Conditions & Etiology Clinical Features Diagnosis Management Conclusions

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Recurrent Aphthous Stomatitis

•Recurrent aphthous stomatitis (RAS) is the most common

•The term aphthous is derived from a Greek word aphtha,

•It is estimated that at least 1 in 5 individuals

•The disorder most commonly affects young adults

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

The 2 forms are

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

Table 1: Classification of Recurrent Aphthous Stomatitis (RAS)

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

Behçet's syndrome is a multi-system vasculitis of unknown aetiology

After skin-cleansing with

Development of a papule or pustule at the site of insertion

•The pathogenesis of aphthous stomatitis is largely unknown, although an

•IFN-γ, IL-2, IL-4, IL-5, but not for IL-10,

•TH2-related genes are not overexpressed in RAS tissues.

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

•Predisposing factors for aphthous stomatitis include:

CBC, complete blood cell

CBC, complete blood cell simple aphthosis

•In children, the association of symmetric enamel

the number of CD patients

•Thus, the literature reviewed does support an association between

•The oral ulcers that are a manifestation of CD would respond

Vitamin B12 deficiency

studies indicate that

This variation may be

Vitamin B12 deficiency

•Case reports indicate that some cases of RAS in patients with

•Treatment with vitamin B12 may be of benefit

•First described in 1987, PFAPA syndrome is a clinical entity characterized

1) a recurrent fever of early onset (<5 years) with a clockwork periodicity

i) aphthosis, in the absence of upper respiratory

•First described in 1987, PFAPA syndrome is a clinical entity characterized

1) a recurrent fever of early onset (<5 years) with a clockwork periodicity

i) aphthosis, in the absence of upper respiratory

While fever is always

•Intraoral ulcers in PFAPA are generally described

•By definition, the diagnosis of PFAPA syndrome requires also exclusion

In a preliminary experience, 83% of patients with mevalonate kinase

•Importantly, although oral aphthosis was found less frequently in monogenic

OR for a (+) genetic test

This score identified

•Therefore, because PFAPA syndrome is far more prevalent than the

serum procalcitonin concentrations

6 PFAPA syndrome patients

Sampling on the 3rd-5th day of fever.

During febrile episodes in PFAPA

•In conclusion, it seems that the question that needs to be addressed

“How to differentiate PFAPA from other similar diseases causing

•Infections with human immunodeficiency virus, Yersinia, tuberculosis, and

•Antibiotics, β-blockers, angiotensin-converting enzyme inhibitors, and

•Multivariate paired analysis has revealed a significant association between

•Drug-induced ulcers are located usually on the side of the tongue,

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

Aphthous stomatitis presents as shallow, round to oval,

There are 3 different clinical variants of RAS:

1) minor aphthous stomatitis (Mikulicz aphthae), These ulcers are

2) major aphthous stomatitis Notice the

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

Shah K, Ann Allergy Asthma Immunol. 2016;117(4):341-343

•Diagnostic testing is suggested