Recurrent aphthous stomatitis

Introduction
Classification
Immunopathogenesis
Underlying Conditions & Etiology
Clinical features
Diagnosis
Management
Conclusions
Recurrent Aphthous Stomatitis
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it

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

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

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 Aphthous Stomatitis : Classification

Recurrent aphthous
stomatitis has
and 3 morphological
types.
The 2 forms are
simple and complex
aphthosis,
and the
are:
minor, major and
ulcers.
2011;17:755e770.
Complex aphthosis
refers to the
persistent
presence of
≥ 3 ulcers,
associated genital
lesions, and
resultant serious
disability,
in the absence
of Behçet disease.
Keogan MT. Clin Exp
Immunol.
2009;156:1e11.

Recurrent aphthous
stomatitis has
and 3 morphological
types.
The 2 forms are
simple and complex
aphthosis,
and the
are:
minor, major and
ulcers.
2011;17:755e770.
Ocular lesions (uveitis),
erythema nodosum,
pustular lesions,
cutaneous pathergy
(nodule formation after
intradermal injection
of saline), and
bizarre neurologic
findings also occur in
Behcet Disease, setting
this condition apart.
Mat MC. Clin Dermatol.
2014;32:435e442.

RAS has been classified
based on the
size and evolution
of lesions
into 3 types:
1. minor aphthae
(Mikulicz aphthae),
2. major aphthae
(Sutton disease, also
referred to as
periadenitis mucosa
necrotica recurrens),
3. herpetiform ulcerations.
The superficial lesions are
rounded, with a yellow-colored
slough (pantano) and surrounding
erythema, and may result
in scarring and, rarely,
tissue destruction.
Morphological Types

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.
Patients presenting with
recurrent orogenital ulcers
may have
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.
complex aphthosis,
Behçet's disease,
secondary complex aphthosis
(e.g. Reiter's syndrome, Crohn's disease,
cyclical neutropenia) or
non-aphthous disease (including bullous disorders,
erythema multiforme, erosive lichen planus).

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.

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.
•TH2-related genes are not overexpressed in RAS tissues.
•A role for oral microbiota in disease pathogenesis
also been proposed. Bankvall M. J Oral Microbiol. 2014;6:25739.
•IFN-γ, IL-2, IL-4, IL-5, but not for IL-10,
suggesting defective tissue healing responses.
•tumor necrosis factor a (TNF-a) and
•interleukin 15 (IL-15),
lesion are
infiltrated
X

•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:
predisposing factors

Recurrent Aphthous Stomatitis: underlying conditions
Shah K,
Ann Allergy
Asthma Immunol.
2016;117(4):341-343
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.

Recurrent Aphthous Stomatitis: underlying conditions
Shah K,
Ann Allergy
Asthma Immunol.
2016;117(4):341-343
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.
simple aphthosis
may be associated with celiac disease
and gluten sensitivity

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.
+
≈

The
prevalence
of CD in
pateints with
RAS
has been
reported
between
4% and 40%
of cases
Celiac disease (CD)
Is RAS associated with Celiac Disease?
Baccaglini L. Oral Dis. 2011;17:755-770.

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)

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?
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.
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.
Is RAS associated with Vitamin B12 deficiency?

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.
58 patients
suffering from RAS:
•31 a sublingual dose
of 1000 mcg
of vitamin B(12),
•27 placebo
for 6 months
% patients free of ulceration
after 6 months of treatment
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
vitamin B12 placebo
74.1%
32%
p <0.01

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.
58 patients
suffering from RAS:
•31 a sublingual dose
of 1000 mcg
of vitamin B(12),
•27 placebo
for 6 months
% patients free of ulceration
after 6 months of treatment
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
vitamin B12 placebo
74.1%
32%
p <0.01
This significant
response to
vitamin B12
was independent
of initial
blood B12 level.

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,
ii) cervical adenitis,
iii) pharyngitis,
in the absence of upper respiratory
tract infections and cyclic neutropenia.

•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,
ii) cervical adenitis,
iii) pharyngitis,
in the absence of upper respiratory
tract infections and cyclic neutropenia.
The primary complaint is the periodic fever
rather than the stomatitis.

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.

OR for a (+) genetic test
40 –
30 –
20 –
10 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
4.1
(+) FH of
periodic
fever
thoracic
pain
4.6
abdominal
pain
33.1
diarrhea
3.3
oral
aphthosis
0.2
A diagnostic score for molecular analysis of hereditary
autoinflammatory syndromes with periodic fever
in children. Gattorno M. Arthritis Rheum. 2008;58(6):1823-32.
A total of 228
consecutive
patients with a
clinical history
of periodic fever
screened for
mutations in the
MVK,
TNFRSF1A, and
MEFV genes.
P = 0.039 P = 0.05
P < 0.001
P = 0.028
P = 0.007

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.

•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.
Differentiating PFAPA syndrome from monogenic periodic
fevers. Gattorno M, Pediatrics. 2009;124(4):e721-8.

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.
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.
During febrile episodes in PFAPA
patients, leukocyte counts and
serum concentrations of CRP were
invariably and significantly elevated
to a median of 11,200/μl
(range 9,600–18,800/μl)
and 7.9 mg/dl (range 5.7–14.7 mg/dl),
respectively.
an association of high serum CRP with
an elevated leukocyte count and
undetectable levels of procalcitonin
may be used as a criterion
to distinguish an inflammatory attack
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.

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),
2) major aphthous stomatitis
(Sutton disease or
periadenitis mucosa necrotica recurrens), or
3) herpetiform ulceration.
These ulcers are
relatively
small and shallow.
Notice the
significant
difference in
depth and
irregular shape
of a major ulcer
in comparison to
a minor ulcer.

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

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.

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.
•Lasers or chemical cauterization may provide fairly rapid pain relief,
attributed to disruption of local nerve endings
or reduction in inflammatory mediators.
However, some of these therapies require
repeated dental visits, which are not
feasible long-term or for frequent RAS.

•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.

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.

Recurrent aphthous stomatitis

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