Oral Ulcerative Lesions
Giovanni Lodi, Elena Varoni, Jairo Robledo-Sierra,
Alessandro Villa, and Mats Jontell
Abstract
Ulcers are the most common lesions affecting
the oral mucosa, and they can be ascribed to
a plethora of local or systemic conditions,
making differential diagnosis pivotal and
often difficult. As oral ulcers, they can be a
manifestation of local or systemic conditions
of very different nature and severity, including
trauma (mechanical, chemical, thermal), drug
reactions, immune-mediated diseases, infec-
tions, and neoplasms; a careful differential
diagnosis is mandatory. Recurrent aphthous
stomatitis (RAS) is the most frequent ulcera-
tive disorder of the oral cavity, affecting 10–20%
of the general population. RAS lesions typically
present as round or oval shallow ulcers of the
nonkeratinized mucosa, with a yellow-grayish
G. Lodi (*) • E. Varoni
Dipartimento di Scienze Biomediche, Chirurgiche e
Odontoiatriche, Università degli Studi di Milano, Milan,
Italy
e-mail: giovanni.lodi@unimi.it; elena.varoni@unimi.it
J. Robledo-Sierra • M. Jontell
Department of Oral Medicine and Pathology, Sahlgrenska
Academy, University of Gothenburg, Gothenburg, Sweden
e-mail: jairo.robledo@odontologi.gu.se;
robledosierra@gmail.com; mats.jontell@odontologi.gu.se
A. Villa
Division of Oral Medicine and Dentistry, Brigham and
Women’s Hospital & Dana Farber Cancer Center and
Department of Oral Medicine, Infection and Immunity,
Harvard School of Dental Medicine, Boston, MA, USA
e-mail: avilla@bwh.harvard.edu; avilla@partners.org
# Springer International Publishing AG 2017
C.S. Farah et al. (eds.), Contemporary Oral Medicine,
https://doi.org/10.1007/978-3-319-28100-1_12-1
fibrin pseudomembrane and a characteristic
erythematous halo. They usually appear first
in childhood or adolescence, in subjects without
other systemic signs. RAS may present in four
main forms based on its clinical appearance
(minor, major, herpetiform, and severe), and
its management depends on the frequency and
severity of the lesions. RAS episodes are self-
limiting and in most cases do not need treat-
ment. For severe and painful cases, the aim of
therapy is to control pain and to reduce the
frequency of episodes. Topical corticosteroids
are typically first-line treatment, but they do not
affect the rate of recurrence. Less frequently,
aphthous stomatitis can be associated with a
number of systemic conditions, including gas-
trointestinal disorders, in particular inflamma-
tory bowel diseases and celiac disease, Behçet
syndrome, food allergy, and deficiencies of
micronutrients, mainly vitamin B12, folate, fer-
ritin, and iron. In all these cases, the detection
of oral lesions can lead to an early diagnosis of
the underlying condition, which management
requires a multi-specialist approach.
Keywords
Oral ulcer • Oral ulcerative disease • Oral ulcer-
ative conditions • Recurrent aphthous ulcera-
tion • Recurrent aphthous stomatitis •
Aphthous-like ulcers • Crohn’s disease • Celiac
disease • Inflammatory bowel disease • Behçet
syndrome • Food allergy • Micronutrient
deficiency
1
2 G. Lodi et al.

Contents drug reactions (Table 1). In addition, an ulcerative

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
lesion can result from different processes and
etiopathogenic mechanisms, such as bullae or
Ulcerative Lesions of the Mouth . . . . . . . . . . . . . . . . . . . . 3 vesicle formation and rupture, external forces,
Reactive Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . . . 3
Immunological Ulcerative Conditions . . . . . . . . . . . . . . . . 6 host-related factors, or alteration of epithelial pro-
Infective Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . . . 6 liferation and differentiation (Fig. 1). Thus, differ-
Neoplastic Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . 8 ential diagnosis of an oral ulcer is a key skill in
Recurrent Aphthous Stomatitis (RAS) . . . . . . . . . . . . . 8 oral medicine practice, since similar lesions can
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 have a deeply different impact on the well-being
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 of patients, and a misdiagnosis can bring very
Diagnosis and Clinical Presentation . . . . . . . . . . . . . . . . . . 9
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
serious consequences. This is the case with a
chronic traumatic ulcer of the tongue, a very com-
Aphthous Stomatitis Associated with Systemic
mon lesion that can share a number of features
Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 with a squamous cell carcinoma of the same site,
Behçet Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 as they are both long-lasting, pauci-symptomatic,
Food Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 indurated, single lesions (Fig. 2). While the
Recurrent Aphthous Stomatitis and Micronutrient first resolves spontaneously once the traumatic
Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 cause has been removed, the latter is potentially
Conclusions and Future Directions . . . . . . . . . . . . . . . . . 27 lethal (see chapters on “▶ White and Red Lesions
of the Oral Mucosa” and “▶ Oral Mucosal
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Malignancies”).
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Although histological examination and spe-
cific laboratory tests are often mandatory, a careful
clinical examination, associated with thorough
Introduction history taking, can provide insights into the nature
of an oral ulcer. Important clinical features in
An ulcer of the mouth results from the complete investigating a patient affected by ulcer(s) of the
loss of epithelium which exposes the underlying mouth range from:
connective tissues. When the loss is limited to the
epithelial layers, the term erosion is preferred,
although such distinction can be difficult on the • Number of lesions, single as for oral cancer or
basis of clinical investigation only. multiple as for herpetic infection
As indicated by a number of epidemiological • Specific localization, as for aphthae which pre-
studies (Axéll 1976; Carrard et al. 2011; García- fer nonkeratinized mucosa or chronic trau-
Pola Vallejo et al. 2002; Pentenero et al. 2008; matic ulcer, in relation with a scabrous or
Shulman et al. 2004), ulcerations are among the rough surface
most common lesions affecting the oral mucosa. • Duration, with a recent onset typical of acute
This is probably due to the fact that not only do conditions, or extensive length for chronic
many of the most common oral conditions present lesions, including oral cancer
as ulcerative lesions (see other chapters on • Presence of a blister preceding the ulcer, a
“▶ Oral Lichen Planus,” “▶ Oral Vesicular and feature of immune-mediated conditions
Bullous Lesions,” and “▶ Oral and Maxillofacial (bulla) or viral infection (vesicle)
Viral Infections”) but also that an ulcer can be the • Presence of other mucosal changes, as for oral
manifestation of a large number of local and sys- lichen planus, which ulcers are always associ-
temic conditions, including viral, bacterial, ated with other manifestations of the disease,
parasite and fungal infections, immune-mediated and extraoral signs, as for mucocutaneous con-
diseases, neoplasms, hematological disorders, ditions with frequent skin involvement (i.e.,
trauma (mechanical, chemical, thermal), and pemphigus, erythema multiforme)
Oral Ulcerative Lesions 3

Table 1 Causes of oral ulcers (Modified from Scully and Table 1 (continued)
Felix 2005)
Gastrointestinal disease
Local causes Celiac disease
Trauma Crohn’s disease
Oral Appliances Ulcerative colitis
Iatrogenic Miscellaneous uncommon diseases
Non-accidental injury Eosinophilic ulcer
Self-inflicted Giant cell arteritis
Sharp teeth or restorations Hypereosinophilic syndrome
Burns Lupus erythematosus
Chemical Necrotizing sialometaplasia
Cold Periarteritis nodosa
Electric Reiter’s syndrome
Heat Sweet’s syndrome
Radiation Wegener’s granulomatosis
Recurrent aphthae
Infections
Acute necrotizing gingivitis In addition, some conditions allow a diagnosis
Chickenpox based on pattern recognition (Sackett et al. 1991),
Deep mycoses which is based on a very distinctive presentation
Hand, foot, and mouth disease of lesions. This is the case of recurrent aphthous
Herpangina stomatitis, probably the most common ulcerative
Herpetic stomatitis condition affecting the oral mucosa (Fig. 3)
HIV (Mortazavi et al. 2016).
Infectious mononucleosis
Syphilis
Tuberculosis Ulcerative Lesions of the Mouth
Drugs
Cytotoxic drugs Reactive Ulcerative Conditions
Nicorandil, NSAIDs
Many others
Reactive oral ulcerations are those resulting from
Malignant neoplasms
trauma affecting the mucosal lining of the mouth
Oral
and represent a large group of conditions of dif-
Encroaching from antrum
Systemic disease
ferent origin and nature, including self-inflicted
Mucocutaneous disease lesions, iatrogenic disorders, and drug-related
Behçet syndrome adverse effects. Reactive oral ulcerations are diag-
Chronic ulcerative stomatitis nosed on the basis of clinical presentation, history,
Epidermolysis bullosa and identification of the trauma responsible, and
Erythema multiforme they resolve spontaneously once the causative
Lichen planus factor has been identified and removed.
Pemphigus vulgaris Mechanical trauma, mostly chronic, can result
Subepithelial immune blistering diseases (pemphigoid from sharp margins of teeth or a prosthesis, an
and variants, dermatitis herpetiformis, linear IgA disease) incongruous denture flange, or self-biting, includ-
Hematological disorders ing factitious injuries, which are more common
Anemia
in subject with psychological or psychiatric prob-
Gammopathies
lems (Fig. 4). Thermal lesions are also common;
Hematinic deficiencies
in most cases they are the consequence of contact
Leukemia and myelodysplastic syndrome
of the oral mucosa, especially of the palate, with
Neutropenia and other white cell dyscrasias
particularly hot drinks or solid food, particularly
(continued)
4 G. Lodi et al.

Normal mucous membrane

Epithelium

Lamina propria

a b c d

Mucosal ulcer

Complete breach of epithelium

Fig. 1 Mechanisms leading to the formation of a mucosal
ulcer. Oral ulcers can be the result of (a) external trauma of
different nature (mechanical, thermal, chemical, radiant),
(b) inflammatory processes leading to atrophy of the muco-
sal lining, (c) rupture of vesicles or bullae of different
origin affecting the mucosa, and (d) disturbances of epi-
thelial proliferation and differentiation, leading to architec-
tural abnormalities of the mucosa (Original drawing by
Dr. Hala Al Janaby, Perth WA, Australia)

Fig. 2 Two persistent lesions of different nature: a chronic traumatic ulcer (a) and an oral squamous cell carcinoma (b)

when heated in a microwave oven (Cowan et al. agents, either acidic or alkaline, responsible
2013). The so-called pizza burn is the most for damage of the oral mucosa include dental
typical lesion of this kind (Nahlieli et al. 1999). materials (hydrogen peroxide or whitening gels),
Chemicals can also cause oral ulceration. Caustic local or systemic medications such as aspirin,
Oral Ulcerative Lesions 5

(i) Traumatic ulcer

Acute solitary ulcers (ii) Necrotizing sialometaplasia

Acute ulcers

Acute multiple ulcers (i) Primary herpetic gingivostomatitis

(i) Long-standing traumatic ulcers
(ii) Necrotizing sialometaplasia
(iii) Eosinophilic ulcer
Chronic solitary ulcers (iv) Ulcerative squamous cell carcinoma
(v) Cytomegalovirus-associated ulceration
(vi) Tuberculous ulcer
Oral Ulcers Chronic ulcers (vii) Syphilitic ulceration (chancre)
(viii) Deep fungal ulceration
(Histoplasmosis, Blastomycosis, and
Mucormycosis)
(ii) Varicella-Zoster Virus infection
(iii) Herpangina
(iv) Hand-foot-and-mouth disease
(v) Erythema multiforme
(vi) Necrotizing ulcerative gingivitis
(vii) Oral hypersentivity reactions
(viii) Plasma cell gingivostomatitis
(ix) Chemotherapy-related ulcers

(i) Pemphigus vulgaris

(ii) Mucous membrane pemphigoid
Chronic multiple ulcers (iii) Bullous pemphigoid
(iv) Lichen planus
(v) Linear IgA disease

(i) Recurrent aphthous stomatitis

Recurrent ulcers Solitary/multiple ulcers (ii) Recurrent herpes stomatitis
(iii) Herpes-associated erythema multiforme
(iv) Cyclic neutropenia
(v) Behçet’s disease

Fig. 3 Diagnostic flowchart for oral ulcerative lesions (Mortazavi et al. 2016)

Fig. 4 Self-inflicted ulcer of the tongue in a child (a) and teenager (b) with psychiatric disorders

bisphosphonates, antipsychotic drugs, antihyper- Immunological Ulcerative Conditions

tensive medications, mouthwashes, recreational
drugs, and non-pharmaceutical substances (hair
products, battery acid) (Figs. 5 and 6) (Gilvetti
2010). Exposure to ionizing radiation for the treat-
ment of head and neck cancer almost invariably
leads to mucositis, a diffuse and painful ulceration
of the oral mucosa (Fig. 7).
Immunological conditions affecting the oral
mucosa are a group of diseases which are
common causes of oral ulcerations, comprising
aphthous stomatitis, oral lichen planus, mucous
membrane pemphigoid, pemphigus vulgaris,
erythema multiforme, lupus erythematosus, and
6 G. Lodi et al.
Fig. 5 Tongue ulceration as an adverse effect to heart
arrhythmia medication (sotalol) (Image courtesy of Profes-
sor Camile Farah, Perth Oral Medicine and Dental Sleep
Centre, Perth WA, Australia)
Fig. 6 Chemical burn on buccal mucosa caused by local
application of aspirin tablets
other less common disorders. Although ulcers can
be a distinctive feature, they are never, with the
exception of aphthous stomatitis, the only sign of
the disease but part of a more complex picture,
which can comprise other oral manifestations,
such as white striae in oral lichen planus
(Alrashdan et al. 2016) and lupus erythematosus
(Brennan et al. 2005), blisters in pemphigoid and
pemphigus (McMillan et al. 2015; Taylor et al.
2015), lip crusting in erythema multiforme
(Samim et al. 2013), and desquamative gingivitis
(Lo Russo et al. 2008) in most of the
Fig. 7 Mucositis in a patient undergoing head and neck
radiotherapy
aforementioned conditions. Additionally, extra-
oral signs can be part of the clinical presentation
of immunological conditions causing oral ulcers,
and often they are a key feature of differential
diagnosis. In particular, cutaneous lesions can be
pathognomonic as in the case of target lesions in
erythema multiforme or strongly suggestive as in
papulae for lichen planus or blisters in pemphigus
vulgaris (Fig. 8). More detailed discussion around
these conditions can be found in chapters on
“▶ Oral Lichen Planus,” “▶ Oral Vesicular and
Bullous Lesions,” and “▶ Oral and Maxillofacial
Viral Infections,” “▶ White and Red Lesions of
the Oral Mucosa” and “▶ Oral Manifestations of
Systemic Diseases and Their Treatments.”
Infective Ulcerative Conditions
Many infections of the oral mucosa, either viral,
bacterial, or mycotic, can present as ulcerative
conditions affecting the oral cavity.
Among viral infections, those caused by
some of the human herpesviruses (HHV), the
Herpesviridae known to infect humans, in partic-
ular herpes simplex virus 1 and 2 (or HHV1 and
HHV2) and varicella zoster virus (or HHV3), are
the most common causes of infective ulcers of
the mouth. Herpes simplex infection of the oral
mucosa, either primary or recurrent, presents
with oral ulcerations which, although different in
severity and extension, have some characteristic
features which allow a clinical diagnosis in most
Oral Ulcerative Lesions
Fig. 8 Immunological ulcerative conditions. (a) Lichen planus, (b) pemphigus vulgaris, (c) mucous membrane
pemphigoid, and (d) erythema multiforme
cases (Balasubramaniam et al. 2014). These ulcers
appear as small (few millimeters) shallow round
lesions, originating from vesicles, surrounded by
an erythematous halo, which can coalesce to form
larger and irregular ulcers (Fig. 8). Often painful,
they have a predilection for keratinized surfaces,
although they can affect any oral mucosa.
Secondary infection of varicella zoster virus,
which is less common and often associated with
7
immunocompromised status, causes similar
lesions, often with a unilateral distribution.
Although less common, bacterial and mycotic
infections can also cause ulcerative lesions of
the mouth. Among them the most common
causal agents are Treponema pallidum (syphilis),
Toxoplasma gondii (toxoplasmosis), Mycobacte-
rium tuberculosis (tuberculosis), and Neisseria
gonorrhoeae (see chapters on “▶ Oral Fungal
8 G. Lodi et al.

Fig. 9 Neoplastic ulcerative conditions. (a) Low-grade salivary adenocarcinoma and (b) diffuse large B cell lymphoma

Table 2 Types of recurrent aphthous stomatitis

Type Size Duration
Minor <1.0 cm 7–10 days
Major >1.0 cm Weeks, often with scarring
Herpetiform Few mm (usually >10 ulcers) 7–10 days
Severe <1.0 cm (same as minor) Continuously

Infections” and “▶ Non-Odontogenic Bacterial RAS may present in four main forms based on its
Infections” for more detail). clinical appearance: minor, major, herpetiform,
and severe (Table 2).

Neoplastic Ulcerative Conditions

A single, indurated ulcer is a common presen-
tation of oral cancer and must be carefully differ-
entiated from traumatic or bacterial ulcers. Oral
squamous cell carcinoma represents more than
90% of cancer of the mouth (Chi et al. 2015);
however a range of other malignancies of the
oral cavity may also present as ulcers, including
neoplasms of the salivary glands, hematologic
malignancies, metastatic neoplasms, and Kaposi
sarcoma (Fig. 9).
Recurrent Aphthous Stomatitis (RAS)
Recurrent aphthous stomatitis (RAS), or “canker
sores,” is a common oral mucosal disease affect-
ing 10–20% of the general population. It is char-
acterized by recurring ulcers of the oral mucosa
usually manifesting first in childhood or adoles-
cence in patients with no other systemic diseases.
Epidemiology
RAS usually initially develops in individuals
between 10 and 19 years of age and becomes
less common with time (Ship et al. 2000). Cases
of RAS that become more severe with age may be
indicative of an underlying systemic condition
(e.g., Behçet disease, connective tissue disorders,
hematologic diseases) and merit further investiga-
tion. The incidence of RAS ranges between 5%
and 50% and is dependent on the socioeconomic
status and ethnicity of patients (Ship 1962). The
prevalence of RAS in children has been reported
to be as high as 40% (Miller et al. 1980) and is
influenced by family history; individuals whose
parents have a history of RAS are at higher risk of
developing RAS compared to those who have a
negative family history (90% vs. 20%) (Ship
1972). In addition, children with a high socioeco-
nomic status are five times more likely to develop
RAS (Crivelli et al. 1988; Gallo et al. 2009).
Oral Ulcerative Lesions
Etiopathogenesis
The etiology of RAS is multifactorial and not
yet well understood. Theories in the past have
associated RAS with several bacterial and viral
infections, such as varicella zoster virus (VZV),
cytomegalovirus (CMV), and human herpes
virus (HHV) 6 and 7, oral streptococci, and
Helicobacter pylori, although none of these have
been confirmed and data remain inconclusive (Lin
et al. 2005; Pedersen and Hornsleth 1993; Victoria
et al. 2003).
Common risk and triggering factors associated
with RAS include local factors (e.g., smoking
cessation and trauma), hematologic or immuno-
logic defects, and genetics. Heredity may play a
role as both twins and children with parents
affected by RAS are more prone to develop the
disease (Miller et al. 1980). Several specific
human leukocyte antigens (HLAs) have been
associated in RAS patients (HLA-A2, HLA-B5,
HLA-B12, HLA-B44, HLA-B51, HLA-B52,
HLA-DR2, HLA-DR7, and HLA-DQ series)
confirming the inherited nature of this disease
(Albanidou-Farmaki et al. 2008).
RAS is considered an immuno-mediated
condition; however specific abnormalities of the
immune system have not yet been identified
(Baccaglini et al. 2008). Immunoglobulin serum
levels and natural killer cells are usually within
normal ranges in patients with RAS. Studies have
shown defects of cell-mediated immunity with an
alteration in the CD4+:CD8+ T lymphocyte ratio
(Preeti et al. 2011). Specifically, CD4+ cells are
more frequent in the pre-ulcer and healing phases,
while CD8+ cell levels are higher when the ulcer
is present (Bachtiar et al. 1998; Sun et al. 2000). A
dysfunction of the mucosal cytokine cascade has
been associated with RAS with a subsequent
increased cell-mediated immune response and
local ulceration of the oral mucosa. Increased
levels of interleukin-2 (IL-2), IL-4, IL-5, inter-
feron-γ, and tumor necrosis factor-α in aphthous
ulcers and raised levels of circulating IL-6 have
been found in patients with RAS (Boras et al.
2006; Buno et al. 1998; Pekiner et al. 2012; Yama-
moto et al. 1994). In addition, RAS has been
linked to genetic factors, specifically those genes
9
controlling the release of pro-inflammatory cyto-
kines IL-1B and IL-6 (Bazrafshani et al. 2002).
Other possible precipitating factors for RAS
include nutritional deficiencies, psychological
stress, anxiety, hormonal fluctuations, allergy
to certain foods, and sodium lauryl sulfate-
containing toothpaste (Akintoye and Greenberg
2014). Conditions that may present with RAS
include micronutrient deficiencies, Behçet dis-
ease, celiac disease, inflammatory bowel disease,
and HIV disease (see below).
Diagnosis and Clinical Presentation
The diagnosis of RAS is generally made through
the patient’s history and clinical presentation.
Biopsy is not indicated, although it may be helpful
in atypical cases to rule out other conditions. Oral
ulcers typically develop in the first two decades of
life, and the frequency of developing recurrent
lesions decreases during the third decade. In
some rare cases, the severity and frequency of
RAS can increase in the elderly. RAS typically
presents as round or oval shallow ulcers of
the nonkeratinized mucosa with a yellow-grayish
fibrin pseudomembrane with a characteristic ery-
thematous halo. The labial and buccal mucosae
are the most commonly affected sites. Major RAS
may also involve other sites such as the tongue
dorsum, hard palate, soft palate, and palatoglossal
and palatopharyngeal arches. Sometimes a burn-
ing sensation or tingling may precede the devel-
opment of oral ulcers with localized erythema.
Crunchy, spicy, acidic food and certain beverages
may make eating, speaking, and swallowing un-
comfortable. Four main forms exist: minor,
herpetiform, major, and severe (Table 2).
Minor aphthous stomatitis (Fig. 10) represents
the most common form; minor aphthae are less
than 1 cm in diameter and can be single or multi-
ple. The ulcers are round, shallow, and often sym-
metric. Once present, they can be painful (mainly
during the first 3–4 days, exacerbated with oral
function), usually last 7–10 days, and heal without
scarring. The majority of patients with RAS report
one to six lesions at a time with few recurring
episodes in 1 year.
10 G. Lodi et al.

Major aphthous ulcers (Fig. 11) are larger

Fig. 10 Minor recurrent aphthous stomatitis on the buccal
mucosa
Fig. 11 Major recurrent aphthous stomatitis on the soft
palate
(usually >1.0 cm in diameter), deep, extremely
painful lesions, which interfere with speech and
eating, and last for weeks or months. In some
cases, major aphthae may be misdiagnosed as a
vesiculobullous disorder, squamous cell carci-
noma, or granulomatous disease. The lesions
may heal with scar formation. In the most severe
cases, hospitalization for intravenous feeding may
be required.
Herpetiform aphthous stomatitis (Fig. 12) is a
rare variant, with multiple small ulcers, measuring
few millimeters, with a crop-like appearance that
usually coalesce to form a large lesion with irreg-
ular margin similar to HSV-related ulcers. The
overall appearance is identical to the minor
aphthous ulcers (although smaller in size), and
these also heal within 7–10 days.
Severe aphthous ulcers (Fig. 13) are a variant
in which patients are almost never ulcer-free,
and they are often associated with chronic pain,
malnutrition, and weight loss. Patients typically
develop new ulcers when the previous ones are
healing. Both the keratinized and nonkeratinized
mucosa may be affected. In HIV patients, severe
recurrent aphthous ulcers are often larger than
1.0 cm in diameter.
In cases of atypical RAS (such as in older
individuals with new episodes or in patients with
other/new systemic symptoms), laboratory tests
may be helpful. A blood workup might be indi-
cated if hematologic deficiencies are suspected
(e.g., low serum levels of vitamin B12, folate,
ferritin, and iron) or in HIV patients with a CD4

Fig. 12 Herpetiform recurrent aphthous stomatitis on the soft palate (a) and lower labial mucosa (b)
Oral Ulcerative Lesions
count below 100/mm3 (Crivelli et al. 1988).
Tissue biopsies may be obtained to rule out
vesiculobullous disorders (e.g., mucous mem-
brane pemphigoid or pemphigus) or granuloma-
tous diseases (e.g., sarcoidosis or Crohn’s
disease).
Management
The management of RAS depends on the fre-
quency and severity of the lesions. In many
cases (especially for the minor form) treatment is
not necessary as the pain is tolerable and does
not interfere with the daily life activities of
the patient (Fig. 14). The main therapeutic goal
for severe and painful cases is to reduce the
frequency of the episodes and control the pain.
Patients who report one to two outbreaks a year
Fig. 13 Severe recurrent aphthous stomatitis on the uvula,
palatoglossal arches, and soft palate
Fig. 14 Spontaneous healing of an aphthous lesion on the buccal mucosa at initial presentation (a) and 10 days later (b)
11
may be instructed to use over-the-counter local
anesthetics (such as 10% benzocaine), viscous
lidocaine, or mucoadhesive agents such as poly-
vinylpyrrolidone sodium hyaluronate (Gelclair ®,
Helsinn Healthcare SA, Lugano, Switzerland)
and methylcellulose paste (Orabase Paste ®
Colgate, Colgate-Palmolive Company, New York).
Amlexanox is a prescription medication with
anti-inflammatory properties incorporated in a
mucoadhesive agent that has shown some effec-
tiveness (OraDisc A™, Access Pharmaceuticals
Inc., Addison, TX). Reassurance and patient
education on the condition are also indicated.
Patients with more frequent and severe episodes
may be treated with topical corticosteroids and
other immunosuppressive agents to shorten the
duration and size of the ulcers (Baccaglini et al.
2011; Scully et al. 2003). High-potency topical
steroids (betamethasone, clobetasol, or fluo-
cinonide) are usually applied on the affected
area two to three times daily after meals. Larger
and recalcitrant ulcers (such as the ones observed
in the major form) can be treated by intralesional
therapy such as triamcinolone injections at
10 mg per cm2 of ulceration (Table 3). Systemic
therapy for severe outbreaks that do not respond
to topical measures can be managed with pred-
nisone (usually at 1 mg/kg), pentoxifylline, dap-
sone, colchicine, azathioprine, or thalidomide.
Due to possible side effects with these medica-
tions, patients should be carefully monitored
long term. Thalidomide is indicated for patients
with severe or major RAS cases who failed other
treatments (Hello et al. 2010). Thalidomide
12 G. Lodi et al.

Table 3 Topical anesthetics and immunosuppressive agents used for management of recurrent aphthous stomatitis
Topical anesthetics for pain Instructions
control
Benzocaine 10% Apply to the affected site, 3–4 times a day
Benzydamine hydrochloride Swish 5–15 mL and spit out, 3–4 times a day
0.15%
Dyclonine hydrochloride 1%
Viscous lidocaine 2% Viscous lidocaine may be mixed in equal volume with diphenhydramine,
aluminum/magnesium, and bismuth subsalicylate
Topical immunosuppressive Instructions
agents
Triamcinolone 0.1% in Apply to affected site 2–3 times daily; no drink or food intake for 20–30 min
methylcellulose paste afterward
Clobetasol 0.05% gel
Betamethasone 0.05% gel
Fluocinolone 0.05% gel
Dexamethasone elixir 0.5 mg/ Dispense 300 mL; swish 5 mL for 3–4 min (timed) and spit out, 3–4 times a day;
5 mL no drink or food intake for 20–30 min afterward
Clobetasol 0.05% solution
(compounded)
Steroid injection with 5–10 mg triamcinolone per cm2 of ulceration
triamcinolone (into the ulcer)

causes severe birth defects, and as such women
of childbearing age must agree to use two forms
of contraception. In the United States, clinicians
prescribing thalidomide must be registered in the
REMS (Risk Evaluation and Mitigation Strat-
egy) program for thalidomide. Noteworthy, the
evidence supporting such treatments are scarce,
as showed by a Cochrane review in 2012
(Table 4).
together with oral aphthous lesions, the clinical
suspicion of IBD or CD should be considered
(Scully 2006). In these patients, aphthous lesions
can be either proper extraintestinal manifestations
of the gastrointestinal disturbance or signs of
nutritional and hematological deficiencies due to
the malabsorption of micronutrients, a typical
complication of such conditions (Slebioda et al.
2014) (Table 5).

Inflammatory Bowel Disease (IBD)

Aphthous Stomatitis Associated
with Systemic Conditions
Gastrointestinal Disorders
Aphthous lesions are often reported as common in
inflammatory bowel diseases (IBD) and celiac
disease (CD); thus it is not unusual that a patient
with an established gastrointestinal disorder
reports recurring oral ulcers with an aspect
recalling common aphthae. In addition, aphthous
lesions can represent early features of these intes-
tinal conditions and thus suggestive of these dis-
eases (Fasano and Catassi 2012; Kalla et al. 2014).
For such reasons, when a patient reports abdom-
inal pain, persistent diarrhea, and weight loss,
Inflammatory bowel disease (IBD) is a broad term
to define chronic or recurring inflammation of the
gastrointestinal tract, due to the dysregulation of
mucosa immune cells. IBD include two types of
chronic intestinal disorders, Crohn’s disease and
ulcerative colitis, two chronic inflammatory dis-
eases of the digestive tract likely to originate from
an inappropriate inflammatory response to intes-
tinal microbes in a genetically susceptible host
which can be differentiated by means of the loca-
tion of lesions along the gastrointestinal tract, as
well as histological features (Abraham and Cho
2009). About one-third of IBD patients also dis-
play a wide range of extraintestinal manifesta-
tions, which mainly involve the joints, skin, oral
mucosa, eyes, and liver. Focusing on oral
Oral Ulcerative Lesions 13

Table 4 Systemic treatments for recurrent aphthous stomatitis (From Brocklehurst et al. 2012)
Cochrane
Drug Dose conclusions Adverse effects
Immunomodulatory/ 1.3–1.6 beta- 10 mg twice per day for Insufficient No reporting of
anti-inflammatory glucan 20 days evidence to adverse effects
support or refute
the use
Clofazimine 100 mg daily for 30 days, Insufficient An increase in
then 100 mg every other evidence to cutaneous adverse
day support or refute effects
the use
Colchicine 0.5 mg three times per day Insufficient Gastrointestinal
evidence to adverse effects
support or refute
the use
Levamisole 150 mg per day Inconsistent Headache, nausea,
evidence heartburn/weakness,
regarding the diarrhea, metallic taste
effectiveness of
levamisole
Leukotriene 10 mg montelukast orally Insufficient Equal drug-related
receptor daily for 1 month evidence to adverse effect for
antagonist followed by alternate days support or refute those treated with
for the second month the use montelukast and
placebo
Pentoxifylline 400 mg three times daily Insufficient Dizziness, headaches,
for 60 days evidence to stomach upset,
support or refute increased heart rate,
the use and nausea
Prednisone 25 mg with a phased dose Insufficient Gastritis
reduction over a 2-month evidence to
period support or refute
the use
Sulodexide 250 units twice per day for Insufficient No reporting of
40 days and then once a evidence to adverse effects
day for a further 40 days support or refute
the use
Other treatments Camel thorn 40 ml mouthwash Insufficient No reporting of
distillate evidence to adverse effects
support or refute
the use
Individualized n.a. Insufficient No participant needed
homeopathic evidence to to discontinue
medicine support or refute treatment due to
the use adverse events
LongoVital Three tablets per day for Insufficient Adverse events were
(herbal + 4 months evidence to minor
vitamin) support or refute
the use
LongoVital Three tablets per day for Insufficient Very few and mostly
(herbal alone) 4 months evidence to harmless side effects
support or refute
the use
Multivitamin 100 percent of the US Insufficient No reporting of
reference daily intake of evidence to adverse effects
essential vitamin for support or refute
12 months the use
(continued)
14 G. Lodi et al.

Table 4 (continued)
Cochrane
Drug Dose conclusions Adverse effects
Propolis 500 mg per day Insufficient Low rates of minimal
evidence to side effects
support or refute
the use
Sub- 20 mg twice daily for Insufficient No differences in
antimicrobial 90 days evidence to adverse events
doxycycline support or refute compared with
the use placebo
Tetracycline 25 mg four times per day Insufficient No differences in
suspension for 5 days evidence to adverse events
support or refute compared with
the use placebo
Vitamin B12 1000 mcg daily for Insufficient No reporting of
6 months evidence to adverse effects
support or refute
the use

Table 5 Clinical manifestations of inflammatory bowel diseases (IBD), i.e., Crohn’s disease and ulcerative colitis.
Extraintestinal manifestations occur more frequently in patients affected by Crohn’s disease than ulcerative colitis
Gastrointestinal
manifestations
Abdominal pain – altered
bowel habits
Bloody diarrhea, weight
loss
Fever, occasionally
Extraintestinal
manifestations
Joint (arthritis, spondylitis,
back pain)
Liver (hepatobiliary
disorders, fatty liver)
Eye (uveitis)
Skin (pyoderma
gangrenosum)
Oral mucosa
Specific Indurated tag-like lesions
Cobblestoning
Orofacial Crohn’s disease (granulomatosis)
Granular cheilitis
Lip swelling with vertical fissures
Pyostomatitis vegetans
Non specific Aphthous stomatitis
Angular cheilitis
Persistent submandibular lymphadenopathy
Recurrent buccal abscesses
Perioral erythema
Malabsorption-related oral changes (glossitis, oral
candidosis, angular cheilitis)

involvement of IBD, pediatricians and dentists
play a critical role in the diagnosis of oral mani-
festations as an early sign of IBD. The prevalence
of IBD is increasing worldwide, and it is higher in
industrialized countries. In particular, the
prevalence of Crohn’s disease has been estimated
to be around 30–50 cases in 100,000 inhabitants
in Western countries (Laranjeira et al. 2015). In
Europe, the prevalence has been attested around
6.3 in 100,000 individuals (Burisch et al. 2013),
Oral Ulcerative Lesions
while in the United States is 201 per 100,000
adults (National Center for Chronic Disease Pre-
vention and Health Promotion 2015). For ulcera-
tive colitis, in Europe, the prevalence is 11.4 per
100,000 individuals (Burisch et al. 2013), while in
the United States is 238 per 100,000 adults, with-
out significant difference between sexes (National
Center for Chronic Disease Prevention and Health
Promotion 2015).
Etiology of IBD, most likely multifactorial, is
still unknown, where several factors such as
smoking habit, diet, and geographic and social
environment play a pivotal, triggering role
(Lankarani et al. 2013). Though not clearly eluci-
dated yet, the pathogenesis appears related to
overly aggressive acquired immune responses to
a subset of commensal enteric bacteria developed
in genetically susceptible hosts and environmen-
tal factors which precipitate the onset or
reactivation of disease (Lankarani et al. 2013).
• Genetics – Four genes (CARD15, SLC22A4
and SLC22A5, DLG5, PPARG) have been
associated with Crohn’s disease and one with
ulcerative colitis (MDR1), which regulate
innate immune responses, bacterial killing,
and immune responses to microbial antigens
and epithelial function (Sartor 2006).
• Immune response – Crohn’s disease and ulcer-
ative colitis show enhanced local recruitment
and retention of effector macrophages, neutro-
phils, and T cells and then activated and able
to release pro-inflammatory cytokines (Sartor
2006). Crohn’s disease is mainly a TH1- and
TH17-mediated process, while ulcerative coli-
tis is an atypical TH2 disorder: although direct
evidence of defective regulatory T-cell func-
tion is lacking in either disease, a plethora of
studies support deficiency in innate immune
responses in Crohn’s disease (Sartor 2006).
• Commensal microbial stimulants – Enteric
microflora can stimulate immune responses
either by functioning as adjuvants, activating
innate immune responses (such as dendritic
cells) or antigens, or stimulating the clonal
expansion of T cells that selectively recog-
nize the antigen through their T-cell receptor
(Sartor 2006).
15
• Environmental triggers – These factors include
smoking, which is protective in ulcerative coli-
tis but detrimental in Crohn’s disease, diet,
the use of antibiotics and nonsteroidal anti-
inflammatory drugs (NSAIDs), stress, and
infection (Sartor 2006).
Even if mechanisms which initiate the onset of
disease or reactivate quiescent IBD are not well
understood, from a broad perspective, these trig-
gering factors alter mucosal barrier integrity,
immune responses, or the luminal microenviron-
ment, each of which has an impact on susceptibil-
ity to inflammation (Sartor 2006).
The basis of an accurate diagnosis of IBD
is focused on clinical presentation, colonoscopy,
and biopsy of ulcer tissue (Scully 2006), in com-
bination, because there is no unique manifestation
of IBD. Colonoscopy reveals inflammatory lesions
surrounded by normal mucosa, which initially
appear as spherical aphthoid erosions, then per-
sisting invariant or progressing to form ulcers
(Jung 2012). If mucosal inflammation and edema
increase in correlation to activity of IBD, the
intestinal mucosa shows a nodular surface with
a cobblestone appearance (Jung 2012). Crohn’s
disease can affect any part of the digestive tract,
while ulcerative colitis is limited to the colon and
rectum (Baumgart and Sandborn 2007). Biopsy is
usually performed on areas beyond erosions or
ulcers, which has the highest potential for detecting
granuloma, in turn difficult to find in the cob-
blestone mucosa (Jung 2012). Histologically,
ulcerative colitis displays chronic inflammatory
lesions restricted to the mucosal epithelium,
while Crohn’s disease affects the full thickness
of the bowel wall (Baumgart and Sandborn 2007).
Epidemiology
The global prevalence of the oral manifestation of
IBD in adults varies from 5% to 50% (Katsanos
et al. 2015; Lankarani et al. 2013); this wide range
results from several reports that also include non-
specific oral manifestations of IBD, which might
be related to medical treatment or derived from
other etiologies. IBD prevalence is higher in chil-
dren than in adults and in Crohn’s disease than in
16
ulcerative colitis (Katsanos et al. 2015; Lankarani
et al. 2013; Pittock et al. 2001).
Aphthae may occur in 10–30% of adult
patients with Crohn’s disease and in a signifi-
cantly smaller proportion of subjects with ulcera-
tive colitis (Akintoye and Greenberg 2014;
Katsanos et al. 2015; Lankarani et al. 2013; Singh
et al. 2015). This frequency is not significantly
different than in the unaffected population
(Bradley et al. 2004). However, in a recent
Turkish study, aphthous stomatitis (40.2%) was
the most common mucocutaneous manifestation
reported in both ulcerative colitis (44.6%) and
Crohn’s disease (33.3%), and no relationship
was found between mucocutaneous manifesta-
tions and age, duration of disease, activity indices,
or location of IBD (Topaloğlu Demir et al. 2014).
Etiopathogenesis
The pathogenesis of the IBD oral manifestations
is still unclear. In Crohn’s disease, pathological
features of aphthae include, as highlighted by oral
mucosa biopsies: (i) granuloma formation, simi-
larly to that observed in intestinal lesions, (ii) the
presence of lymphocytes around vessels in the
subepithelial tissue and of plasma cells con-
taining IgM, and (iii) a decreased heat shock
Fig. 15 Aphthous-like lesions in the mouth of patients suffering from Crohn’s disease involving the buccal sulcus (a) and
buccal mucosa (b)
G. Lodi et al.
protein 27 (HSP27) expression compared to con-
trols (Katsanos et al. 2015).
Only weak evidence supports a genetic pre-
disposition for oral manifestations, though studies
show altered patterns of T-cell cytokine pro-
duction leading to loss of tolerance to oral anti-
gens, association between HLA-B27 and IBD
extraintestinal symptoms, and DRB1*0103 allele
increase in patients with ulcerative colitis com-
plaining of oral ulcers (Katsanos et al. 2015).
Increased frequency of oral manifestations
among IBD patients has been recently correlated
with aberrations in the oral salivary microbiota,
where Bacteroidetes was significantly increased
with a concurrent decrease in Proteobacteria
(Katsanos et al. 2015).
Clinical Presentation
Crohn’s oral ulcers can resemble RAS (Fig. 15),
but they may also have distinct characteristics
such as indurated borders and histological fea-
tures of granulomatous nature (Akintoye and
Greenberg 2014). In addition, they appear
more extensive and painful than those seen in
other aphthous forms (Bradley et al. 2004).
Although the oral lesions might be more severe
at the time of active disease, the association
between oral aphthosis and IBD disease activity
Oral Ulcerative Lesions
is not clear, and data are still controversial
(Akintoye and Greenberg 2014; Katsanos et al.
2015).
IBD can display other oral lesions different
from aphthous ulcers (Katsanos et al. 2015;
Lankarani et al. 2013), which are more common
in patients suffering from Crohn’s disease than
in subjects with ulcerative colitis, particularly
in Crohn’s disease patients with proximal
gastrointestinal tract and/or perianal involve-
ment (Lankarani et al. 2013) These include cob-
blestoned buccal mucosa, granular cheilitis,
and granular gingival swelling, similar to oro-
facial granulomatosis (Katsanos et al. 2015).
Pyostomatitis vegetans is another specific finding,
which can be typically associated with both
Crohn’s disease and ulcerative colitis (Katsanos
et al. 2015).
Subjects with extraintestinal manifestations
of IBD seem to be more likely to suffer from
a combination of these; thus IBD patients with
aphthae may have concomitantly extraintestinal
manifestations including peripheral and axial
arthropathies, erythema nodosum, uveitis, and pri-
mary sclerosing cholangitis (Veloso et al. 1996).
In addition, aphthous ulcers, as extraintestinal
manifestations of IBD, usually parallel the disease
activity of IBD, occurring during active intestinal
disease and responding favorably to its treatment
(Veloso et al. 1996).
Oral Lesions in the Diagnosis of IBD
Normally, intestinal involvement precedes oral
manifestations; however in 5–10% of IBD cases
and in up to 60% in patients with Crohn’s disease
(Lankarani et al. 2013), the specific oral mani-
festations may precede gastrointestinal symp-
toms by many years. It has been estimated that
10–37% of children who receive a diagnosis
of orofacial granulomatosis may start suffering
from Crohn’s disease in the following years
(Katsanos et al. 2015). In the presence of
oral manifestations, histological examination is
only recommended for lesions suggestive of
granulomatosis. Although it is not possible to
distinguish orofacial granulomatosis and oral
Crohn’s disease just on the basis of histolo-
gical features, referral to a gastroenterologist is
17
recommended when the presence of granulomatosis
is confirmed in a patient with bowel features sug-
gestive of IBD (such as persistent diarrhea).
To date, it is not possible to distinguish patients
with RAS from those with aphthous-like ulcers of
the mouth who are likely to develop IBD. Since
the buccal epithelium of children with Crohn’s
disease appears immunologically more reactive
when compared to that of adult patients, showing
overproduction of certain chemokines (CXCL-8,
CXCL-9, and CXCL-10), it has been hypothe-
sized that these could be used as a screening tool
for children with IBD and RAS (Katsanos et al.
2015). Similarly, levels of tumor necrosis factor-α
(TNF-α), found to be higher in the mucosa of
patients with Crohn’s disease and oral aphthae,
could also contribute to recognize immune-
mediated oral ulcers associated with this condition
(Bradley et al. 2004).
Patient Management
Management of Crohn’s disease is based mainly
on anti-inflammatory and immunosuppressive
topical and systemic therapies as well as dietary
advice, including elimination of cinnamon, ben-
zoate, glutaminate, cocoa, and with micronu-
trient supplementation. The medical therapies for
Crohn’s disease are usually sufficient also for
the control of oral manifestations of the disease
(Veloso et al. 1996). Oral aphthosis usually
resolves in most treated children, despite that up
to 30% of affected patients, especially pediatric
ones, may continue to manifest oral lesions after
disease control (Lankarani et al. 2013). In such
cases where specific oral manifestations, such
as cobblestoned mucosa, granulomatosis, and
lip and facial swelling, are refractory and uncom-
fortable, as well as in those cases where oral
aphthae are recurrent and severe, local treatment
for pain and discomfort relief is indicated. It can
be easily achieved by topical application
of anesthetic drugs (lidocaine gel) and anti-
inflammatory drugs, mainly steroids, such as tri-
amcinolone or dexamethasone ointments, up to
three times/day for about 10 days (Akintoye and
Greenberg 2014). Systemic or intralesional ste-
roids and other immunomodulators are also
recommended for severe refractory and/or
18
persistent cases not responding to topical thera-
pies (Akintoye and Greenberg 2014).
Celiac Disease (CD)
CD is a chronic, multisystem, immune-mediated
disease of the small intestine triggered in geneti-
cally predisposed individuals by exposure to
dietary gluten, particularly to gliadin, a specific
gluten protein which belongs to the group of pro-
lamins (Gujral et al. 2012). The latter are plant
storage proline-rich proteins present in wheat, rye,
and barley. Originally thought to affect white
Europeans solely, CD is nowadays widely distrib-
uted globally, becoming a frequent food intoler-
ance. The worldwide mean prevalence of CD
has been reported to range from 0.5% to 1%,
depending on the population under investigation.
The prevalence of 1% reflects figures in Europe
and North America (Gujral et al. 2012). In the
general population, high-risk groups for CD
are those with familial history of biopsy-proven
CD or affected by type 1 diabetes or systemic
autoimmune disorders such as thyroiditis (Gujral
et al. 2012).
The pathogenesis of CD is dependent on both a
strong genetic predisposition and environmental
triggers. The primary environmental factor is the
ingestion of food containing gluten, while the
main genetic factor is the class II major histo-
compatibility complex HLA- DQ2 or DQ8
genes, also shared in patients with type 1 diabetes
and other systemic autoimmune disorders (Gujral
et al. 2012; Lionetti et al. 2014). A recent random-
ized clinical trial on infants at high risk of CD
indicated that a high-risk HLA genotype was a
pivotal predictor of disease, while the delayed
introduction of gluten in the diet did not modify
risk of developing the disease, although it was
associated with a delayed onset of disease
(Lionetti et al. 2014).
Several pathways have been involved in CD
pathogenesis. Besides the direct toxicity of gliadin
against the enterocytes, gliadin peptides appeared
to upregulate stress molecules in intraepithelial
lymphocytes, promoting a lymphocyte-mediated
cytotoxic response against enterocytes (Barker
and Liu 2008). Moreover, the structure of gliadin
itself, unusually rich in proline residues, results
G. Lodi et al.
in an intrinsic resistance to gastrointestinal diges-
tion, along with a preference for binding to
DQ2 molecules, further mediating autoimmune
inflammation (Barker and Liu 2008). An additio-
nal, pivotal pathway for CD development involves
transglutaminase (tTG), a calcium-dependent
enzyme. tTG has the main molecular role of
cross-linking and deamidation of gliadin, pro-
ducing an epitope that binds efficiently to DQ2
and is recognized by gut-derived gliadin-reactive
CD-4+ T cells (Barker and Liu 2008). tTG auto-
antibodies, as immunoglobulin A (IgA), occur
because antigen-presenting cells “inadvertently”
target tTG-gliadin complexes, resulting in an
immune reaction against both gliadin and tTG
(Barker and Liu 2008). tTG IgA, detectable in
the serum of almost all CD individuals is also
associated to extraintestinal symptoms of CD,
which can deposit in the liver, kidney, lymph
nodes, and muscles (Gujral et al. 2012). tTG IgA
disappears slowly from the bloodstream, when the
patient is under a gluten-free diet.
Epidemiology
Weight loss or other signs of malabsorption may
be suggestive of the presence of CD in a patient
with oral aphthae, even though this disease has
been detected in less than 5 percent of patients
with RAS referred to a hospital clinic for exami-
nation (Scully 2006).
Dental enamel defects and oral aphthae repre-
sent the two most common oral manifestations
associated with CD. The prevalence of dental
enamel defects in CD patients with mixed or per-
manent dentition ranges widely, from 9.5% to
95.9%, while in patients with deciduous teeth, it
decreases to 5.8–13.3% (Rashid et al. 2011). Such
difference is due to the difference in time of erup-
tion, and the fact that crowns of permanent teeth
develop within the seventh year of age after the
introduction of dietary gluten in the child, and the
development of deciduous teeth occurs primarily
in utero, in the absence of gluten gastrointestinal
exposure of the fetus. Regarding oral aphthae,
figures are difficult to extrapolate, since several
reports fail to specify the exact diagnostic criteria
used. Some controlled studies, however,
suggested a higher frequency of recurrent oral
Oral Ulcerative Lesions 19

ulcers in CD patients compared with control
groups (Baccaglini et al. 2011; de Carvalho et al.
2015). Excluding case reports, studies investigat-
ing the prevalence of CD in patients with RAS
provide a broad range of estimates, ranging from
4% to 40% (Baccaglini et al. 2011). Conversely,
studies on the prevalence of RAS in patients with
CD show that the number of subjects who have
RAS ranges from 3% to 61% (Baccaglini et al.
2011), while in a large survey of a Canadian
population with biopsy-proven CD, 16% of chil-
dren and 26% of adults reported suffering from
recurrent oral ulcers (Rashid et al. 2011).
Etiopathogenesis
The exact cause of aphthous ulcers in CD is
unknown, although they have been related mainly
with hematinic deficiencies, including low serum
iron, folic acid, and vitamin B12 due to malab-
sorption in patients with untreated CD (see recur-
rent aphthous stomatitis and deficiencies of
micronutrients). Similarly, the exact mechanism
leading to dental defects is largely unclear.
Immune-mediated damage has been proposed
to be the primary cause, though nutritional dis-
turbances, putatively producing hypocalcemia
and vitamin insufficiencies, as well as gluten-
dependent stimulation of oral naïve lymphocytes
cannot be completely ruled out (Rashid et al. 2011).
Clinical Presentation
Aphthous ulcers and dental enamel defects belong
to a group of well-documented dental and oral
mucosa manifestations of CD (Table 6). The pres-
ence of recurrent aphthous lesions, especially in
individuals with dental enamel defects, is now
considered a significant condition for suspecting
CD. Interestingly, in around one-fifth of cases,
oral ulcers can represent the first sign of CD;
several authors have reported cases of patients
presenting with recurrent oral ulceration who sub-
sequently received a diagnosis of CD (Baccaglini
et al. 2011). Clinically, the features of oral
aphthous lesions in CD are not far from the
classical picture of idiopathic oral aphthae; they
have been mostly described as minor RAS
although, as mentioned above, most studies have
not reported well-defined criteria for diagnosis of
RAS (Baccaglini et al. 2011).
If CD appears in children, when permanent
teeth are developing, abnormalities in the struc-
ture of the dental enamel can arise, usually
symmetrically and chronologically in all four
quadrants. Typical aspects include enamel hypo-
plasia and hypomineralization, with pitting,
grooving, and sometimes complete loss of enamel
(Rashid et al. 2011). A classification of these CD
dental defects has been developed (Table 6) (Aine
et al. 1990), which are less frequent in adults with
CD, due to the fact that CD onset may have
occurred after dentition development or may
have had affected restored or extracted teeth
(Rashid et al. 2011).
Oral Lesions in the Diagnosis of Celiac
Disease
The clinician should always consider CD among
differential diagnosis in any patient presenting
with dental enamel defects and recurrent aphthous
lesions, since their association is considered spe-
cific to CD. The presence of a hereditary case of
CD or concomitant autoimmune diseases, espe-
cially type 1 diabetes, will further increase the
probability of CD.

Table 6 Oral and dental lesions associated with celiac disease

Oral mucosa lesions Dental lesions
Recurrent aphthous ulcers Delayed dental eruption
Cheilosis Enamel defects (classification according to Aine (de Carvalho et al. 2015):
Atrophic glossitis Grade I: defects in color of enamel – single or multiple cream, yellow or brown
opacities
Grade II: slight structural defects – rough enamel surface, horizontal grooves, shallow
pits
Grade III: evident structural defects – deep horizontal grooves and vertical pits
Grade III: severe structural defects – shape changes
20
Children with a documented history of RAS
and signs of malabsorption should undergo a den-
tal examination and, if presenting with enamel
defects, should be referred to a gastroenterologist
who may confirm the diagnosis of CD by per-
forming laboratory and instrumental evaluations
(Marty et al. 2016). While awaiting diagnostic
confirmation of CD, the clinician should not rec-
ommend a gluten-free diet for the patient (Rashid
et al. 2011).
Oral health-care providers play an important
role in detecting both classical and atypical cases
of CD, contributing to decreasing diagnostic
delay, which is still high. Delay in CD diagnosis
can lead to a plethora of complications, from
anemia to osteoporosis and, in worse cases, repro-
ductive disorders and increased risk of developing
intestinal malignancies such as small intestine
adenocarcinoma and lymphoma (Green and
Cellier 2007; Rashid et al. 2011).
Patient Management
Currently, the main therapeutic intervention for
CD is a gluten-free diet. Adherence to a gluten-
free diet improves gastrointestinal symptoms
and may also reduce frequency and severity of
aphthous ulcers, although this has not been con-
firmed in all reports (de Carvalho et al. 2015). The
response to therapy is poor in up 30% of patients
(refractory form of CD), mainly due to lack of
compliance with diet (Green and Cellier 2007).
Severe and persistent aphthae can often
be managed as idiopathic forms of RAS, using
topical antiseptic and steroid medicaments
and reserving systemic therapies for severe,
non-respondent cases.
Behçet Syndrome
Behçet syndrome or Behçet disease (BD) is an
inflammatory multisystemic disorder with vascu-
lar, articular, gastrointestinal, neurologic, urogen-
ital, pulmonary, and cardiac involvement. The
disease was first described in 1937 by the Turkish
dermatologist, Hulusi Behçet, as a triad of symp-
toms, namely, recurrent oral ulcers, genital ulcers,
and uveitis (Behçet 1937).
G. Lodi et al.
Epidemiology
The onset of BD usually occurs in the third or
fourth decade of life. BD is seen worldwide,
although it is a rare condition. It has a typical
geographic distribution, with an increased preva-
lence in people with ancestors who lived in the
Silk Route, which extended from Japan to the
Middle East and Mediterranean countries. Turkey
has the highest prevalence, with a prevalence in
the population aged 12 years or older of
420/100,000 (Azizlerli et al. 2003). The disease
is rarely observed in Western countries: the prev-
alence of BD is approximately 0.64/100,000 in
the United Kingdom and 0.12–0.33/100,000 in
the United States (Sakane et al. 1999). The overall
gender distribution has been reported to be
roughly equal, but some regional variability also
exists. BD shows a male predominance in certain
Middle East and Mediterranean countries and a
female predominance in Japan and South Korea
(Bang et al. 2003).
There is a strong association between the
geographic distribution of human leukocyte
antigen HLA-B51 and the prevalence of BD.
The frequency of HLA-B51 along the Silk Route
ranges between 20% and 25% among the gen-
eral population and 50–80% among patients
with BD (Alpsoy 2016). In contrast, the fre-
quency of HLA-B51 in Northern Europe and the
United States is around 2–8% in the general pop-
ulation and 15% among patients with BD (Dalvi
et al. 2012).
Etiopathogenesis
The etiology of BD is unknown. The most widely
accepted theory behind its pathogenesis is that
an environmental stimulus elicits an abnormal
immune response in a genetically susceptible
host. The presence of HLA-B51 is still considered
the strongest susceptibility factor for BD, as
subjects carrying this gene have a signifi-
cantly increased risk of developing this condition
(de Menthon et al. 2009). The presence of
HLA-B51 alone is not sufficient to explain the
etiology of the disease in all cases; only 60% of
patients with BD express HLA-B51, and this
HLA allele is seen frequently in the absence of
the disease (Keogan 2009). These data suggest
Oral Ulcerative Lesions
that other susceptibility genes or genetic varia-
tions may also be involved.
It has also been suggested that environmental
factors may play a pivotal role in the pathogenesis
of BD. The presence of HSV-1-infected cells and
the load of Streptococcus species, particularly
S. sanguinis, have been found to be higher in
patients with BD compared to controls. However,
their role in the etiology of the disease remains to
be determined. A clinical hypothesis is that infec-
tious agents and associated stress proteins found
in the oral cavity of patients with BD induce cross-
reactivity with host cells and stimulate the prolif-
eration of autoreactive T-cell clones. Heat shock
proteins can be recognized by pattern recognition
receptors as an endogenous “danger” signal, lead-
ing to activation of innate and adaptive immune
responses. They also increase the expression of
adhesion molecules on endothelial cells. Over-
expression of pro-inflammatory cytokines (mainly
IL-17, IL-23, and interferon-γ) appears to be
responsible for the enhanced inflammatory reac-
tion. Increased neutrophil activity and neutrophil
infiltration in affected organs may be caused by
increased IL-17 response. This inflammatory pro-
cess eventually results in tissue damage and vas-
culitis (Keogan 2009).
Clinical Presentation
BD is characterized by unpredictable exacerba-
tions and remissions and presents with a wide
spectrum of clinical manifestations. It is associ-
ated with increased mortality due to involvement
of the central nervous system, lungs and large
vessels, bowel perforation, and gastrointestinal
hemorrhage (Keogan 2009). Mucocutaneous
lesions constitute the hallmark of BD. Oral ulcers
are the most common feature, affecting 92–100%
of the patients, followed by genital ulcers
(57–93%) and cutaneous lesions (38–99%)
(Alpsoy et al. 2007). Ocular and articular involve-
ments are also frequent traits of the disease.
No specific histopathological features have
been described in BD. Large vessel involvement
is generally characterized by vasculitis with
thrombosis or aneurysm, while the mucocutane-
ous lesions often display leukocytoclastic vascu-
litis or a neutrophilic vascular reaction.
21
Oral ulcers – This is usually the first manifes-
tation of BD. They are characterized by recurrent
and debilitating ulcerations of the oral mucosa,
clinically indistinguishable from RAS. They can
be found anywhere in the oral cavity, but the
most commonly affected sites are the labial and
buccal mucosa, tongue, soft palate, and orophar-
ynx. The minor form is by far the most common,
followed by the major and herpetiform variants in
decreasing order, as described in a large study
which reported a high frequency of mixed forms
(Gurler et al. 1997). Patients with BD tend to
have a higher number of simultaneous ulcers,
more frequent recurrences (Main and Chamber-
lain 1992), higher incidence of major aphthae
(Krause et al. 1999), and more involvement of
the soft palate and oropharynx (Alpsoy et al.
2007) than patients with RAS (Fig. 16).
Genital ulcers – Genital ulcers are rarely the
presenting feature of BD. The ulcerations may be
preceded by a papule or pustule and appear similar
to oral aphthae but occur less often and scar more
frequently. Associated pain may cause difficulty
with micturition, dyspareunia, and even hinder
walking (Senusi et al. 2015). In women, ulcers
most commonly affect the labia, but lesions in the
vaginal mucosa and cervix may also occur. In
men, the scrotum is regularly involved, although
involvement of the shaft and glans penis is also
frequent. Ulcers in the groin, perineum, and peri-
anal area are seen in both genders.
Fig. 16 Aphthous-like lesion in the mouth of a patient
with Behçet syndrome involving the lateral dorsal tongue
22
Ocular lesions – Ocular disease is seen in
30–70% of patients and is more frequent and
severe in men. Typically, ocular symptoms begin
after the onset of oral ulceration. However, intra-
ocular inflammation is the presenting feature in
approximately 20% of cases. Ocular disease is
bilateral in 85% of patients and runs a relapsing
course in 95% of cases (Kitaichi et al. 2007).
Severity may differ between the eyes. Panuveitis,
posterior uveitis, anterior uveitis, retinal vasculi-
tis, optic neuritis, and retinal vein occlusion are
the most common features and cause significant
morbidity. Formation of a hypopyon, a visible
layer of pus in the anterior chamber, is seen in
Fig. 17 Ocular lesions of Behçet syndrome. (a) Mild
conjunctival injection and hypopyon, (b) retinal hemor-
rhage associated with retinal vasculitis, and (c) retinal
G. Lodi et al.
12% of patients and rarely in other conditions
(Tugal-Tutkun et al. 2004) (Fig. 17).
Cutaneous lesions – Skin lesions are described
in approximately 80% of patients with
BD. Erythema nodosum-like lesions are seen in
30% of patients, mainly on the lower extremities
but also on the face, neck, and buttocks. Lesions
rarely ulcerate, resolve within 2–3 weeks, and
can cause post-inflammatory hyperpigmentation.
While clinically similar to classical erythema
nodosum, lesions of BD differ histologically, with
evidence of vasculitis (Kim and LeBoit 2000).
Other common skin lesions include papulopustular
lesions, superficial thrombophlebitis, and pathergy.
vasculitis (demonstrated by fluorescein angiography)
(Images courtesy of Dr. Hiroshi Goto, Tokyo Medical
University)
Oral Ulcerative Lesions 23

Diagnosis irreversible organ damage, which occurs espe-

Since there are no pathognomonic signs nor any
specific laboratory, radiologic, or histologic find-
ings for BD, the diagnosis is purely based on
the recognition of clinical findings together with
the exclusion of other conditions. Despite large
research efforts over the past few decades, no
universally accepted diagnostic criteria exist for
BD, as documented by the existence of 17 sets of
diagnosis/classification criteria (Davatchi et al.
2015). The criteria proposed in 1990 by the Inter-
national Study Group (ISG) for Behçet Disease
(International Study Group for Behçet Disease
1990) remain the most widely used among experts
(Table 7). Recently, the International Team for the
Revision of the International Criteria for Behçet
Disease (ICBD) published new criteria (Interna-
tional Team for the Revision of the International
Criteria for Behçet Disease 2014), where oral
ulcers, genital ulcers, and ocular lesions receive
two points each and other manifestations (cutane-
ous lesions, neurologic and vascular involvement,
and positive skin pathergy test) receive one point
each. If a patient receives four points or more, the
patient is diagnosed with BD. It has been shown
that the ICBD criteria are more sensitive but less
specific than the ISG criteria, which may cause
overdiagnosis.
Patient Management
No curative therapy is currently available for
BD. The ultimate goals of treatment are to prevent
cially in the early stage and active phases of the
disease, and to alleviate symptoms. As for RAS,
the treatment of oral ulcers and other mucocuta-
neous lesions in patients with BD consists mainly
in the use of topical agents, particularly steroids.
However, the number of randomized controlled
trials for targeted therapy is scarce. A recent sys-
tematic review on the management of oral ulcers
in BD concluded that there was insufficient evi-
dence to support or refute the use of any topical or
systemic intervention with regard to pain, episode
duration, or episode frequency associated with
lesions (Taylor et al. 2014).
Systemic therapy with colchicine, pentoxifylline,
and dapsone is often useful when mucocutaneous
lesions are frequent or severe. In refractory cases
thalidomide, azathioprine, or biological agents,
such as tumor necrosis factor-α antagonists
(infliximab, etanercept) and interferon-α, may be
necessary.
Food Allergy
Food allergy has been investigated as a putative
cause of aphthous-like lesions, though scientific
evidence to support this association is still sparse.
Since the oral cavity is subjected to a wide spec-
trum of antigenic agents, including food, allergic
reactions to such antigens might manifest as ulcer-
ative lesions.

Table 7 Diagnostic criteria for Behçet disease by the International Study Group for Behçet Disease
Diagnostic criteria for
Behçet disease
Recurrent oral ulceration Minor aphthous, major aphthous, or herpetiform ulceration observed by the physician/
dentist or patient that recurred at least three times in one 12-month period
Plus, two of the following:
Recurrent genital Aphthous ulceration or scarring observed by the physician or patient
ulceration
Eye lesions Anterior uveitis, posterior uveitis, cells in the vitreous on slit lamp examination, or
retinal vasculitis observed by an ophthalmologist
Cutaneous lesions Erythema nodosum observed by physician or patient, pseudofolliculitis or
papulopustular lesions, or acneiform nodules observed by physician in postadolescent
patients not receiving corticosteroids
Positive pathergy test Read by the physician at 24–48 h
Findings applicable only in the absence of other clinical explanation
24
Epidemiology
A recent epidemiological study, “National Health
and Nutrition Examination Survey (NHANES),”
investigated food allergy prevalence in US chil-
dren in 1988–1994 and in 2005–2006, stratified
by race and/or ethnicity (McGowan et al. 2016).
Nearly 8,000 subjects were included, and the
prevalence of food sensitization was 24.3%, with
no significant differences between the two-time
periods for milk, egg, or peanut sensitization,
while shrimp sensitization decreased markedly
(McGowan et al. 2016). One of the first studies
suggesting a putative role of food allergy or intol-
erance in RAS was a small case series published
in 1986, showing a significant improvement in
6 out 15 patients following dietary withdrawal
(Wright et al. 1986). Subsequent reports that
explored sensitivity to foods, preservatives, or
other agents in patients with a diagnosis of RAS
reported a prevalence of 35–50% (Wardhana and
Datau 2010).
Etiopathogenesis
Although causality between a certain food and
aphthous-like lesions cannot be definitely stated,
the association between allergy and RAS can be
hypothesized on the basis of RAS pathogenesis.
The latter includes immediate type I reactions or
delayed type IV reactions, similar to IgE-mediated
and cell-mediated food hypersensitivity, as is
also supported by histological findings of lesions
(Wardhana and Datau 2010).
Among possible etiological factors, the associ-
ation between immunity to cow’s milk proteins
(CMP) and RAS has been investigated. A strong
association between high levels of serum anti-
CMP IgA, IgG, and IgE antibodies and clinical
manifestations of RAS has been reported (Besu
et al. 2009). In one study, 50 subjects with RAS
(36 with proven increased immunity to CMP
and 14 without this increased immunity) were
enrolled, and data showed that levels of serum
anti-fresh cow’s milk IgA, IgG, and IgE anti-
bodies were significantly higher than levels of
serum anti-fresh goat’s milk in subjects with
RAS with proven increased immunoreactivity to
CMP (Besu et al. 2009). These results indicate
that patients with RAS with increased immunity
G. Lodi et al.
to CMP could consider the use of goat’s milk as
the alternative protein source. The same group
of authors further provided evidence of an etio-
logical role for cow’s milk proteins in RAS deter-
mining the prevalence of increased levels of
serum antibodies to specific cow’s milk proteins
(SCMP), constituents of cheese or whey in sub-
jects with RAS. Results indicated a strong associ-
ation between high levels of serum anti-SCMP
IgA, IgG, and IgE antibodies, especially to
caseins: α-, β-, and κ-casein from cow’s milk and
clinical manifestations of RAS (Besu et al. 2013).
Clinical Presentation
Food allergic reactions in adult patients are similar
to those in children, and they can range in severity
from local and very mild symptoms to systemic
symptoms involving different organs, up to a
fatal outcome (Ballmer-Weber 2015). After oral
mucosal ulcerations (Fig. 18), other putative oral
manifestations of food allergy include cheilitis,
perioral dermatitis, and contact stomatitis (Collet
et al. 2013). Orofacial granulomatosis has also
been associated with intake of certain foods
(McCartan et al. 2011), as well as RAS, although
without a strong cause-effect correlation (Wardhana
and Datau 2010). Oral allergy syndrome (or pol-
len food hypersensitivity syndrome) is considered
to be the commonest form of food allergy
in adults. It occurs in pollen-sensitized subjects
after ingestion of fruits, nuts, and vegetables
containing allergens sharing homology with
Fig. 18 Oral ulceration in a patient suffering from food
allergy involving the buccal mucosa
Oral Ulcerative Lesions
pollen allergens. It is limited to the oropharynx in
pruritus, and clinical presentation may include
tingling, erythema, and swelling of the lip, oral
mucosa, palate, and throat (Ho et al. 2014).
Clinical history and physical examination are
the foundation for the diagnosis of RAS caused by
food allergy. Aphthous lesions, however, do not
differ from the clinical presentation of idiopathic
RAS; thus further elements are required to achieve
a diagnosis of food allergy.
Diagnosis
In a patient with a clinical history suggesting food
allergy, first-line diagnostic testing consists of
skin testing or measurement of serum food-
specific IgE levels or both. However, sensitization
often does not equate to clinical allergy, and a
medically supervised oral food challenge is the
diagnostic gold standard (Abrams and Sicherer
2016). Once the suspected food has been identi-
fied, the best way to demonstrate the association
between food allergy and RAS in a single patient
is probably to verify the resolution or a significant
improvement of aphthous lesions following the
withdrawal of the suspected food from the diet
(elimination diet) and the relapse of the oral ulcers
following rechallenge with the same food. Diet
elimination is not always successful regardless
of whether leukocytes released histamine after
exposure to food antigens is noted or not (Wray
et al. 1982).
Patient Management
Reduction in frequency and severity of recur-
rences and maintenance of remission are among
the goals of therapies to treat RAS. Elimination
diets are frequently utilized in both diagnosis and
management of RAS caused by food allergy, i.e.,
once certain foods are suspected of triggering the
allergic reactions, they are completely omitted
from the diet. Strict exclusion diets result in
improvement and/or resolution of ulcers in a
wide range of cases, from 25% to 75% of patients
(Wardhana and Datau 2010). The success of such
dietary intervention depends on the correct iden-
tification of the food allergens and on the ability
of the patient to avoid them during daily life
(Wardhana and Datau 2010).
25
Besides dietary approaches, treatment of RAS
associated with food allergy involves, once more,
the use of topical and/or systemic treatments,
mainly based on steroid agents, following the
same posology used for idiopathic RAS
(Wardhana and Datau 2010).
Recurrent Aphthous Stomatitis
and Micronutrient Deficiency
The WHO definition of micronutrients states that
“these substances are the magic wands that enable
the body to produce enzymes, hormones and other
substances essential for proper growth and devel-
opment. As tiny as the amounts are, however, the
consequences of their absence are severe” (World
Health Organization 2016). The association of
RAS with deficiencies of different micronutrients
(i.e., vitamin B12, iron, folate, and, more recently,
zinc), as well as the putative role of these sub-
stances in its pathogenesis, has been the subject of
a number of studies since the 1960s (Ship 1962).
At the time, early reports of RAS patients who
improved or even healed following vitamin sup-
plementation led to the idea that RAS could be a
deficiency syndrome, at least in some cases. Since
then, many studies have investigated the fre-
quency of different micronutrient deficiencies
among RAS patients. Nevertheless, a definitive
conclusion has not been reached yet. In fact, dif-
ferences in terms of diagnostic criteria, patient and
control selection, laboratory technique, and nor-
mal value range make data hardly comparable
and to certain extent explain conflicting results
(Table 7).
The deficiency of vitamin B12, a coenzyme for
fat and carbohydrate metabolism, protein synthe-
sis, and hematopoiesis, is responsible for megalo-
blastic anemia, neurological symptoms, chronic
tiredness, and mood disturbance (Vidal-Alaball
et al. 2005). The association of RAS and defi-
ciency of vitamin B12 has been investigated in a
number of controlled and noncontrolled studies
that found a frequency of vitamin B12 deficiency
among RAS patients to range between 0% and
45% (Fig. 19). Another micronutrient of the vita-
min B group often investigated among RAS
26
Fig. 19 Oral ulcers involving the lateral and dorsal sur-
faces of the tongue in a patient suffering from vitamin B12
deficiency
patients is folic acid, a vitamin necessary for
purine and pyrimidine synthesis, erythropoiesis,
and methionine regeneration, the deficiency of
which causes effects similar to that of vitamin
B12 (Fairfield and Fletcher 2002). Patients with
folic acid deficiency can represent up to 51%
of patients suffering from RAS (Table 7). In a
recent meta-analysis including data of over 1100
subjects from 8 case-control studies published
between 1975 and 2014, the rate of vitamin B12
and folic acid deficiencies was significantly
higher in RAS patients, compared with controls
(vitamin B12: odds ratio = 3.75, 95% confidence
interval, 2.38–5.94; folic acid, odds ratio = 7.55,
95% confidence interval, 3.91–14.60) (Chen
et al. 2015).
Similar data are available for iron deficiency
and anemia. Although sideremia, transferrin, and
total iron binding capacity have been the subject
of investigation, ferritin (a protein that stores iron)
is the indicator more commonly used in studies
exploring the association of RAS and iron
deficiency, which has been found below normal
values in a proportion of patients ranging between
7% and 40% (Table 8). In the aforementioned
meta-analysis, ferritin below normal values was
more common in 687 patients with RAS than in
the 583 controls (odds ratio 2.62, 95%; confidence
interval 1.69–4.06) (Chen et al. 2015). Similarly,
although diagnostic criteria for anemia varied
G. Lodi et al.
among studies, up to 60% of patients with RAS
may have hemoglobin values below normal
range, and pooled data from controlled studies
shows a significant association (odds ratio 1.77,
95%; confidence interval 1.12–2.80).
When vitamin B12, folic acid, and iron are
taken together, the proportion of patients suffering
from aphthae, with one or more micronutrient
deficiency, can be as high as 50% (Compilato
et al. 2010) and the difference with control sub-
jects statistically significant (Lopez-Jornet et al.
2014). Notably, anemia and deficiencies of serum
ferritin and folate may be more common in female
patients with RAS, but the same is not true for
vitamin B12 (Burgan et al. 2006).
Little is known about the prevalence of oral
mucosal lesions among subjects with hematinic
deficiencies, although a recent study reported a
22% prevalence of aphthous lesions in patients
deficient in vitamin B12 and vitamin B9 (Andrès
et al. 2016).
Clinical form (minor, major, herpetic, severe),
localization, and severity of lesions do not seem
to be useful in identifying RAS patients with
hematinic deficiencies. In fact, as stated in one
of the first studies investigating this association,
“it was not possible by clinical examination of
the ulcers to separate patients with an underlying
deficiency or disease from those with no such
abnormality” (Wray et al. 1975). In fact, clinical
features are similarly distributed in deficient and
non-deficient subjects (Lopez-Jornet et al. 2014;
Rogers and Hutton 1986; Sun et al. 2015; Wray
et al. 1978).
The role played by diet in RAS onset has been
investigated by comparing nutritional habits
among RAS patients and controls, with reported
significant differences in vitamin B12 and folate
intakes (Kozlak et al. 2010), but not in specific
food categories (Ogura et al. 2001; Ship 1962).
Noteworthy, single or multiple deficiencies of
such micronutrients can be a consequence of
insufficient absorption in the gastrointestinal
tract, a common consequence of chronic inflam-
matory conditions of the bowel, including
Crohn’s disease and celiac disease, disorders
often associated with RAS.
Oral Ulcerative Lesions 27

Table 8 Frequency of micronutrient deficiencies among patients affected by recurrent aphthous stomatitis
Study ID RAS patients Controls Lower reference value
Vitamin B12
Burgan et al. 2006 38/143 (27%) 18/143 (13%) 180 pg/mL
Challacombe et al. 1977 1/40 (2%) 0/26 (0%) 200 ng/L
Compilato et al. 2010 5/32 (15%) 0/29 (0%) 226 pg ⁄mL
Khan et al. 2013 27/60 (45%) 9/60 (15%) 220 pg/mL
Koybasi et al. 2006 12/34 (35%) 0/32 (0%) Not reported
Lopez-Jornet et al. 2014 5/92 (5%) 1/94 (1%) 200 pg/mL
Olson et al. 1982 0/90 (0%) 0/23 (0%) 160 pg/mL
Piskin et al. 2002 8/35 (23%) 0/26 (0%) 200 pg/mL
Porter et al. 1988 2/69 (3%) 2/75 (3%) Not reported
Rogers and Hutton 1986 0/102 (0%) – Not reported
Sun et al. 2015 13/273 (5%) 0/273 (0%) 200 pg/mL
Thongprasom et al. 2002 0/23 (0%) 0/19 (0%) 150 pg/mL
Wray et al. 1975 5/130 (4%) 1/130 (1%) 120 ng/L
Folic acid
Burgan et al. 2006 7/143 (5%) 0/143 (0%) 2.5 ng/mL
Challacombe et al. 1977 7/40 (17%) 4/26 (15%) 5 μg/L
Compilato et al. 2010 6/32 (19%) 0/29 (0%) 2.3 ng ⁄mL
Khan et al. 2013 31/60 (51%) 6/60 (10%) 1.5 ng/mL
Lopez-Jornet et al. 2014 4/92 (4%) 1/94 (1%) 2.7 ng/mL
Piskin et al. 2002 4/35 (11%) 0/26 (0%) 3 μg/L
Rogers and Hutton 1986 22/102 (21%) – Not reported
Sun et al. 2015 7/273 (3%) 0/273 (0%) 4 ng/mL
Wray et al. 1975 7/130 (5%) 3/130 (2%) 2.5 μg/L
Ferritin
Burgan et al. 2006 24/143 (17%) 14/143 (10%) 12 (female) and 14 (male) ng/mL
Compilato et al. 2010 13/32 (40%) 0/29 (0%) 10 (female) and 22 (male) ng⁄mL
Lopez-Jornet et al. 2014 6/92 (7%) 5/94 (5%) 12 ng/mL
Piskin et al. 2002 6/35 (17%) 3/26 (11%) 9 (female) and 18 (male) ng⁄mL
Porter et al. 1988 8/69 (12%) 4/75 (5%) Not reported
Hemoglobin
Babaee et al. 2016 17/28 (60%) 9/28 (32%) 14 (female) and 17 (male) g/dL
Burgan et al. 2006 20/143 (14%) 15/143 (10%)
Challacombe et al. 1977 14/193 (7%) 2/100 (2%) 11.5 (female) and 13 (male) g/dL
Compilato et al. 2010 11/32 (34%) 2/29 (7%) 12.0 (female) and 12.5 (male) g⁄dL
Khan et al. 2013 35/60 (58%) 26/60 (43%) 12 (female) and 14 (male) g/dL
Olson et al. 1982 6/90 (7%) 2/23 (9%) 11 (female) and 13 (male) g/dL
Porter et al. 1988 0/69 (0%) 0/75 (0%) Not reported
Rogers and Hutton 1986 6/102 (6%) – Not reported
Sun et al. 2015 57/273 (21%) 0/273 (0%) 12 (female) and 13 (male) g/dL
Zinc
Bao et al. 2016 33/156 (21.2%) – 70 μg/dL (10.7 μmol/L)
Orbak et al. 2003 17/40 (42.5%) – 95 μg/dL
Ozler 2014 7/25 (28%) 1/25 (4%) 95 μg/dL
Wray 1982 0/20 (0%) – 55 μg/dL
28
More recently, zinc has been the subject of
investigation in groups of patients affected by
RAS. Zinc is an essential micronutrient for
humans. It is a constituent of a large number of
enzymes, fundamental for cell growth, collagen
synthesis, wound healing, and normal function of
reproductive, neurologic, immune, dermatologic,
and gastrointestinal systems. The features of mild
zinc deficiency are frequently nonspecific and
include diarrhea, cognitive and behavioral prob-
lems, hair loss, eye problems, growth retardation,
and recurrent infections (Bao et al. 2016; Shah
et al. 2016). Patients with RAS may have lower
mean levels of zinc in serum compared with con-
trols (Ozturk et al. 2013), as well as higher rate
of zinc deficiency (Table 8). In addition, studies
on animal models, specifically in rats, have
shown that a zinc-deficient diet is associated
with aphthous ulcers and other alterations of
the oral mucosa (Orbak et al. 2007; Seyedmajidi
et al. 2014).
On the basis of anecdotal reports of RAS
patients with documented clinical improvements
following replacement therapy, few randomized
controlled trials have been conducted. One study
treated RAS patients who had experienced at
least three episodes in the previous 12 months,
irrespective of their vitamin serum level, and com-
pared a multivitamin supplement containing the
US reference daily intake of vitamins A, B1, B2,
B3, B5, B6, B9, B12, C, D, and E with placebo
(Lalla et al. 2012). Noteworthy, the multivitamin
supplement showed no benefit either in the sub-
group of participants with low baseline levels of
B12 or in those with a highly frequent form. The
trial was judged at low risk of bias by a Cochrane
review and showed no differences in number or
duration of RAS episodes between the two groups
(Brocklehurst et al. 2012). A separate placebo-
controlled randomized trial tested the effects of a
6-month monotherapy with vitamin B12 (1000
mcg sublingual daily) in patients with RAS.
Again, patients were selected on the basis of the
frequency of aphthous episodes (at least one out-
break every 2 months in the last year), and more
than 80% had normal levels of serum vitamin B12.
G. Lodi et al.
At completion of the trial, the treatment group
reported less pain, a shorter duration of RAS
episodes, and lower frequency of episodes, and
during the last 2 months of treatment, more
participants in the same group were free from
ulcers (Volkov et al. 2009). However, the
Cochrane review assessed the study as unclear
risk of bias and concluded that the evidence pro-
vided was insufficient to support or refute the
use of vitamin B12 for the treatment of RAS
(Brocklehurst et al. 2012).
In conclusion, although a number of patients
with RAS can be affected by micronutrient defi-
ciencies, the evidence presently available does not
offer strong support for routine testing of RAS
patients or treatment with supplements in the
absence of a demonstrated deficiency (in which
case improvement of the oral condition is not
guaranteed).
Conclusions and Future Directions
An ulcer of the mouth can represent a mani-
festation of a number of local and systemic
conditions ranging from self-limiting lesions to
life-threatening diseases. Histological examina-
tion and specific laboratory tests are often essen-
tial elements in the differential diagnosis;
however, clinical features, such as number, local-
ization, duration, and aspect, are fundamental in
the distinguishing of oral ulcerative lesions, and in
many cases they can be sufficient to establish a
definitive diagnosis and start treatment. A proper
management of a patient with oral ulceration needs
an appropriate knowledge of the different mecha-
nisms able to lead to the onset of such mucosal
lesion and, ideally, of the etiopathogenesis of the
underlining diseases. Unfortunately, for many of
them, including common disorders as recurrent
aphthous stomatitis and immunological condi-
tions, very little is known, and for this reason,
treatment is essentially palliative, while a better
understanding of the causes and pathological
mechanisms responsible for them would warrant
a far better management of affected subjects.
Oral Ulcerative Lesions
Cross-References
▶ Clinical Evaluation of Oral Disease
▶ Clinical Immunology in Diagnoses of Maxillo-
facial Disease
▶ Gingival Pathology
▶ Interface Between Oral and Systemic Disease
▶ Laboratory Medicine and Diagnostic Pathology
▶ Non-Odontogenic Bacterial Infections
▶ Oral and Maxillofacial Fungal Infections
▶ Oral and Maxillofacial Viral Infections
▶ Oral Lichen Planus
▶ Oral Manifestations of Systemic Diseases and
Their Treatments
▶ Oral Mucosal Malignancies
▶ Oral Vesicular and Bullous Lesions
▶ Pediatric Oral Medicine
▶ Pharmacotherapeutic Approaches in Oral
Medicine
▶ Soft and Hard Tissue Operative Investigations
in the Diagnosis of Oral Disease
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