Recurrent Aphthous Stomatitis (RAS ), Bechet's Syndrome, Angioedema (Angioneurotic Edema, quincke’s Edema, Giant Urticaria ) and Contact Stomatitis and Dermatitis (Stomatitis and dermatitis venenata )

1. Allergic And Immunologic Diseases Of
Oral Cavity
DR MONIKA NEGI
MDS

2. RECURRENT APHTHOUS
STOMATITIS
(RAS/ aphthae/canker sores)
• It is a common condition which is
characterized by multiple recurrent
small, round or ovoid uIcers with
circumscribed margin,
erythematous halos and yellow or
grey floors, appearing first in
childhood or adolescence.

3. Clinical features
• RAS may affect 5-60yrs.
• Female predominance.
• Seen more predominantly in chiIdren.
• White : black , 3:1
• RAS consist of recurrent bouts of one or
several rounded, shallow, painful oral ulcers at
intervals of a few days to few months.

4. • RAS shows 3 main presentations-
Minor (MiRAS),
Major (MaRAS),
Herpetiform ulcers (HU)

5. Minor recurrent
aphthous stomatitis
(MiRAS)
• Most common affecting
about 80% of RAS
patients,
• Characterized by:
Round or oval shallow
ulcers, 1-5 in no.
• Common sites:
Nonkeratinized mucosa,
labial and buccal mucosa
and floor of the mouth

6. • Shortest duration, Heal
within 10-14 days without
scarring.
• Size: < 5 mm, with a grey-
white pseudomembrane
enveloped by a thin
erythematous halo.
• Burning, itching, or
stinging, development of
erythematous macule
• Most common form of
childhood RAS.

7. Major recurrent aphthous stomatitis (MaRAS)
• Rare, severe form of RAS, also known as
periadenitis mucosa necrotica recurrens.
• Lesions are oval.
• Size: 1 cm -3cm.
• Sites: lips, soft palate, and fauces
• 1-10 in no.

9. • persist for up to 6
weeks.
• Heal with scarring.
• Onset: after
puberty and is
chronic, persisting
for up to 20 or more
years.
• Most frequent
recurrences
• Coalesce into larger
irregular ulcerations
(Scully and Porter, 1989)

10. Major aphthous ulceration with severe scarring

11. Herpetiform ulcers (HU)
• Least common variety of RAS.
• Characterized by:
Multiple recurrent crops of small, painful
ulcers.
• Sites: May be distributed throughout the oral
cavity.
• No.: 100
• Size: 2-3 mm in diameter.
• Late onset.

13. Etiology
• Genetic – (Human Leukocyte Antigen )
(present on cell membrane )
• HLA- DR2, HLA-B12
• Local factors:
– Trauma (self inflicted bites ,oral surgical procedure
etc ..)
• Systemic factors:
- Drugs such as NSAIDS
- Stress

14. - Hematinic (iron, folic acid, or vitamin
B12) deficiencies
- Zinc deficiency
- Bechet's syndrome
- Celiac disease
- Cyclic neutropenia
- Some immunodeficiencies, HIV
- MAGIC syndrome (mouth and genital
ulcers with inflamed cartilage)
- PFAPA syndrome (periodic fever,
aphthous stomatitis, pharyngitis, cervical
adenitis)

15. Immunopathogenesis:
Immune-mediated:
• Mucosal destruction represent T cell mediated
immunologic reaction
• Patients with RAS have increased levels of (Cluster of
differentiation ) CD8+ T-lymphocytes (cyto toxic T cell )
and/or decreased CD4+ T lymphocytes,(suppression of
immune reaction )
• decreased CD4+ to CD8+ T ratio.
• These T-cells secrete various cytokines such as TNF-α,
IL-12 (pro inflammatory cells ), IL-10.(anti inflammatory
)

16. • TNF-α induces the initiation of the
inflammatory process by its chemotactic
effect on neutrophils.
• TNF-α also causes class-I and class-II MHC
expression. (mhc molecules is to bind peptide
fragments derived from pathogens and
display them on the cell surface for
recognition by the appropriate t cells .)

17. • IL-2 levels are markedly increased in the
active stage of RAS.
• IL-2 activates the NK-cells which are
associated with antiviral activity.
• IL-2 shows enhanced cytotoxicity against
fibroblasts, thus there is destruction of the
underlying connective.

18. • In the pre ulcerative and ulcerative stage
there is an increased expression of MHC-I,
II antigens in the basal epithelial cells.
• MHC antigens target these epithelial cells
for attack by cytotoxic (CD8+) T-cells in
the ulcerative stage.

19. Autoimmunity
• Immune deposits do occur especially in
the stratum spinosum, which contributes
to the immune-complex mediated tissue
damage, but is of secondary importance
in the etiopathogenesis of RAS.

20. Microbial Aspects of RAS
(Streptococcus )
• Recently, cross-reactivity between a streptococcal
heat shock protein (hsp) and the oral mucosa has
been demonstrated and significantly elevated
levels of serum antibodies to hsp are also
observed in RAS. (Lehner et al., 1991).
• Association of RAS with adenoviruses &
herpesviruses 1-6 is also seen.
• IgM and IgG antibodies to varicella zoster virus
(VZV) and cytomegalovirus (CMV) may be
elevated in some RAS patients, suggesting
association between them and RAS.

21. Microscopic changes in RAS:-
• Pre ulcerative stage:
lymphocytes infiltrate the epithelium and
edema develops.
• Ulcerative stage:
 Increase of pain.
Development of localized papular swelling
(because of keratinocyte vacuolization)
surrounded by a reactive erythematous
halo representing localized vasculitis with a
dense mononuclear cell infiltrate.

22. The painful papule then ulcerates and a
fibrous membrane covers the ulcer which
is infiltrated mainly by neutrophils,
lymphocytes and plasma cells.
• Healing stage:
Involves epithelial regeneration and
coverage of the ulcer.

23. Histopathologic Features
• Central zone of ulceration covered by
fibrinopurulent membrane
• Increased vascularity, mixed inflammatory
cellular infiltrate
• Numerous mononuclear cells in basilar one
third
• Band of lymphocytes intermixed with histiocytes
in superficial connective tissue and surrounding
deeper blood vessels

26. Behcet’s Disease (BD)
• Also called Behçet's
syndrome, Morbus Behçet, or
Silk Road disease, is a rare
immune-mediated systemic
vasculitis.
• Behçet's disease (BD) was
named in 1937 after the
Turkish dermatologist Hulusi
Behçet, who first described
the triple-symptom complex
of
–recurrent oral aphthous ulcers,
–genital ulcers, and
–uveitis (eye )

27. • Behçet's syndrome is a multisystem disorder
presenting with-
• • Recurrent oral and
• genital ulcerations and
• • Ocular involvement
• • Diagnosis is clinical, based on internationally
agreed diagnostic criteria

28. Clinical Features
• Males and females affected equally
• • Males often have more severe disease
• • Blacks are rarely affected
• Diagnostic Criteria of Behçet's Disease
• • Recurrent oral ulceration plus two of
the following: –
• Recurrent genital ulceration
• –Eye lesions
• –Skin lesions
• –Pathergy test (lesion resistent to
healing )

29. • 1. Orogenital ulceration
• • Recurrent aphthous ulcers
• • Painful, shallow /deep with central necrotic base
• • Singly or in crops
• • Variable size
• • Located anywhere in the oral cavity
• • Persist X 1–2 weeks, subside without scars
• • The genital ulcers –
• • less common, but more specific
• • Painful
• glans penis and urethra, and
• • produce scrotal scars

30. • 2. Skin involvement -80%
• • Folliculitis
• • Erythema nodosum
• • An acne-like exanthem
• • Vasculitis (infrequent)
• • Sweet's syndrome
• • Pyoderma gangrenosum
• • Nonspecific skin inflammatory reactivity to any
scratches or intradermal saline injection (pathergy
test) is a common and specific manifestation.

31. • 3. Eye involvement in 50%
• • Scarring and bilateral pan-uveitis
• • Iritis, posterior uveitis,
• • Retinal vessel occlusions, and
• • Optic neuritis

32. • 4. Joints- 50%
• • Non-deforming arthritis or arthralgias
• • Knees and ankles

33. • 5. Vascular Venous: 50%
• • Superficial/ deep peripheral vein
thrombosis -in 30%
• • Pulmonary emboli –rare
• peripheral arterial aneurysm
• • Arterial thrombosis
• • Pulmonary artery vasculitis (dyspnea,
cough, chest pain, hemoptysis, and pulm
infiltrates)- 5% • DD: Thromboembolic
disease (it requires anti- inflammatory Rx
not thrombolytic therapy

34. • 6. Neurologic involvement (5–10%)
• • Brainstem involvement of serious prognosis
(CNS-Behçet's syndrome).
• • Dural sinus thrombi (20%) (headache and
increased ICP).

35. • 6. Others
• • Gastrointestinal more in Japanese,
resembles Crohn‘s
• • Epididymitis
• • Amyloidosis & glomerulonephritis -
uncommon

36. Investigations
• Mainly nonspecific indices of inflammation
• • Leukocytosis
• • Elevated ESR
• • CRP (c-reactive protein )

37. Treatment
• Mucous membrane involvement :
• • topical glucocorticoids
• • Serious cases- thalidomide
• Mucocutaneous manifestations and arthritis:
• • Colchicine Thrombophlebitis
• • Aspirin

38. • Uveitis and CNS-Behçet's
• • Systemic steroids
• • Azathioprine
• • Cyclosporin Pulmonary or peripheral arterial
aneurysms
• • Cyclophosphamide
• • Anti– TNF

39. Angioedema ,Angioneurotic
Edema,quincke’s Edema ,Giant
Urticaria
• • It is the rapid swelling of the
dermis, subcutaneous tissue,
mucosa and submucosal tissues
• • It is very similar to urticaria (a
rash of round weals on the skin
which itch intensely )
• • Differentiated through history
and examination
• • Etiologies of angioedema are
divided into mast cell mediated
and non-mast cell mediated

41. • Non pitting,
• rapid onset,
• self limiting swelling
• • Results from increased
vascular permability
• • Generally resolves in 24-48
hours
• • But has the potential to ruin
your day (and the patient’s)

42. Types
• The causes of angioedema depend on the
type of angioedema a patient has:
• 1) acute allergic angioedema
• 2) non-allergic drug reactions
• 3) idiopathic angioedema
• 4) hereditary angioedema (HAE) / acquired
C1 inhibitor deficiency

43. Acute allergic angioedema
• • Almost always occurs with
urticaria within 1-2 hours of
exposure to the allergen
• • Nuts, shellfish, milk, eggs
• • Drugs, e.g. penicillin, NSAIDS,
vaccines
• • Radiocontrast media
• • Natural rubber latex e.g. gloves,
catheters
• • Reactions will recur with
repetitive exposures or exposure to
cross-reactive substances

44. Non-allergic drug reactions
• • Onset may be days to months after
taking the medication
• • Commonly ACE inhibitors
• • Cascade of effects via kinin
production and nitric oxide
generation
• • Occurs without urticaria

45. • ACE inhibitors increase bradykinin activity >>>
• Transient vasodilation >>>
• fluid in extracellular space .
• The incidence of angioedema from ACE
inhibitors ranges in the literature from 0.1 to
2.2%

46. Idiopathic angioedema
• • Similar to acute allergic but angioedema
keeps on recurring and often no known cause
is found
• • Usually occurs with urticaria
• • 30-50% of this type of angioedema may be
associated with some types of autoimmune
disorders including SLE

47. Hereditary Angioedema (HAE)
(Activation of complement pathway )
• • 2 types:
• Type 1 and II mutation of C1NH gene ( complement component 1
inhibitor )C1NH is a plasma protein involved in the regulation of
complement cascade has a INHIBITORY proteolytic activity )on
chromosome 11, (encoding C1 inhibitor protein)
• Type III mutation in F12 gene on chromosome 12, (encoding
coagulation factor XII)
• • Type 1 results in low levels and function of circulating C1
inhibitor;
• • Type II has normal levels of C1 inhibitor protein but reduction in
function or non functional .
• • Occurs in 1 in 50,000 males and females (rare)
• • Decreased C1 inhibitor activity leads to excessive kallikrein,
which in turn produces bradykinin, which we know is a potent
vasodilator.

48. Acquired C1 inhibitor deficiency
• • Acquired during life rather than
inherited
• • May be due to B-cell lymphoma or
antibodies against C1 inhibitor
• Seen in association with certain type of
lymphoproliferative disease in patients
who develop specific antiboidies .
• Lymphoid proliferation increases the
consumption of C1-INH,AND THE
ANTIBODIES PREVENT THE BINDING OF
C1-INH TO C1.
• • Treatment is the same as HAE

49. Acquired and Hereditary:
• • Patients often experience no symptoms until
they reach puberty
• • Swellings can occur without any provocation
• • Sometimes local trauma, vigorous exercise,
emotional stress, alcohol, and hormonal
factors
• • Some may get a transitory prodromal non-
itchy rash, headache, visual disturbance or
anxiety
• • Face, hands, arms, legs, genitals, digestive
tract and airway may be affected; swellings
spread slowly
• • Abdominal cramps, nausea, vomiting,
difficulty breathing
• • Urticaria does not usually occur

50. Treatment
• There isn’t much treatment out there…but
AIRWAY! AIRWAY! AIRWAY! HAVE A LOW
THRESHOLD FOR INTUBATION USE CLINICAL
EXAMINATION

51. Investigations
• There are no point-of-care tests!
• Treat what you see and from the patient’s history. Bedside
Fiberoptic laryngoscopy
• Laboratory - Identify underlying cause (help with long
term management): C1 esterase inhibitor (C1-INH) assays
(low/ abnormal in HAE) C4 levels (low in HAE attacks,
usually normal between attacks) serial tryptase levels (may
be elevated in anaphylaxis/ mast cell-mediated
angioedema)
• Imaging CT abdomen may show evidence of angioedema in
patients presenting with abdominal pain:
• CT neck primarily has a role in excluding conditions that
may mimic angioedema (e.g. soft tissue infection)

53. Treatment
• • H1 antihistamine e.g IV chlorpheniramine
10 mg or diphenhydramine 25–50 mg
• • Limited evidence for adding in H2 blocker
e.g ranitidine IV 50mg
• • Intravenous corticosteroids e.g. hydro-
cortisone 200 mg or methylprednisolone 50–
100 mg
• • Adrenaline IM 1:1000

54. • Disposition Consider admission to hospital in the
following situations (Winters et al, 2013):
• • previous history of angioedema
• • tongue edema
• • pharyngeal edema (palate, uvula)
• • laryngeal edema / upper airway oedema
• • lack of improvement during stay in ED Patients
with isolated angioedema of the face or lips and
be usually be observed in ED for 4 to 8 hours for
progression of symptoms, then discharged

55. Contact Stomatitis and Dermatitis
(Stomatitis and dermatitis venenata )
Type of reaction in which
lesion of the skin or
mucous membrane
occurs at a localized site
after repeated contact
with causative agent .

56. • Causative agent
• (chemicals in nature haptens )
• (a small molecule which combines with large carrier protein and
elicit production of antibodies)
• Conjugates with proteins
• Effective
• Intraeipthelial Langerhans cells where the
• Haptens convert into competent antigen
• and presented to T Lymphocytes
• for sensitization and production of IgE WITH SPECIFIC
RECEPTORS .
• Local lymphocytes secrete chemical mediators of inlammation
(lymphokines )
• that produce the clinical and histologic changes .

57. • There are thousands of allergens
• Classified as follows :
 Dental or cosmetic preparations
a. Dentifrices
b. Mouthwashes
c. Denture powder
d. Lipstick ,candy ,cough drops ,chewing gum
 Dental material
a. Rubber dam
b. Vulcanite
c. Acrylic
d. Metal alloy base
 Dental therapeutic agents
a. Alcohols
b. Antibiotics
c. Iodides
d. Phenols
e. Procaine
f. Volatile

58. Clinical features
Itching or burning sensation at
the site of contact
Followed by appearance of
erythema
Vesicles
After rupture of vesicles
,erosion may become extensive
If secondary infection occurs
,lesion may be serious .
In chronic contact ,the skin
may become thickened and
dry .

60. Oral Manifestation
• Rare due to shorter period of contact ,saliva
dilutes and removes many antigens .
• Mucosa becomes inflamed ,edematous
,smooth shiny appearance of the surface .
• Gingiva : uniformly bright in all quardrants ..
• Buccal mucosa :puffy and dark red ,revealing
engorged and ejected superficial capillaries
on closer examination .
• Swollen and edematous features subject to
erosion and ulceration are common on lips
,severe burning sensation ,itching ,stinging
,tingling and edema .

61. • Chronic cases ,affected mucosa is
typically in contact with the causative
agent may be erythematous or white
and hyperkeratotic .
• Chronic contact include
:erosion,widespread erythema
(usually associated with toothpaste
),lip lesions similar to those induced
by chronic irritation (chronic dryness
,scaling ,fissuring or cracking of
vermilion border of lip )

62. Histologic feature
• Intra-and inter-cellular edema of the
epithelium along with vesicle formation
within the epithelium of that of the basement
membrane is usually seen .
• Engorged and dilated vessels
• Lymphocytic and plasma cells infiltration .
• Increased number of eosinophils .

63. Diagnosis
• Patch test may be useful investigation to
identify the causative agent .

64. Treatment
• Discontinuing all contact with the offending
material .

65. Contact stomatitis From Cinnamon
Flavouring
• Cinamon oil used as flavouring agent in
confectionery ,ice cream ,soft drinks,alcholoic
beverages ,mouth wash etc .
• Clinical feature:
• Due to tooth paste –more diffuse ,gingival
enlargment , edema and erythema .
• Erythematous mucositis of buccal mucosa and
tongue ,exfoliative cheilitis ,circumoral dermatitis .
• Chewing gum and candy produce localized lesions
not involving vermilion border of lip or circumoral
skin .
• Oral lesion commonly seen in the buccal mucosa are
oblong hyperekeratotic lesions with an
erythematous base .

66. • Histological features :
• Acanthotic epithelium
• Elongated rete ridges ,thinned
supra papillary plates
,hyperkeratosis and neutrophils .
• Connective tissue exhibit chronic
inflammatory infiltrate .
• Treatment :Discontinuation of
cinnamon

67. Contact Stomatitis from chronic oral
mucosal contact with Dental amalgam
• Acute and chronic
reactions to mercury –
containing compound
have been reported .
• These reactions
clinically represent and
histologically represent
–LP

68. • CLINICAL FEATURES
• In posterior buccal mucosa
,ventral border of tongue
and gingival cuffs adjacent
to subgingival amalgam
restoration .
• Lesion appear white or
erythematous without
striae.

69. • Histological features :
• Similar to LP
• Hydropic degenration of basal
cell layer ,hyperkeratotic or
atrophic epithelium
• Dense band like chronic
inflammatory infiltrate .
• Treatment :removal of amalgam
restoration .

70. Perioral Dermatitis
• Unique inflammatory
skin disease of circum
oral area.
• Idiosyncratic response
.(exogenous
substances such as tar
control toothpaste
,bubblegum ,night
creams ,topical
cortisteroids ).

71. • Clinical Features
• Papules or papulopustules
,involving skin surrounding the
vermilion border of the lips .
• Pruiritis may be present .
• More in women using
cosmetics .

72. • Histological features :
• Chronic lymphohistocytic
dermmatitis .
• (rosacea like pattern )
• Treatment :
• Discontinuation of topical
corticosteroids
• Topical metronidazole ,with or
without topical Tetracycline .

73. Latex allergy
• Type 1
hypersensitivity
reaction .
• Immidiate reaction
are urticaria
,rhinitis and
edema around
eyelids .
• Treatment :
• Non latex products
or cotton liners .