Immunologic ulcers

L5 100Immunologic
5‫ مدسن س‬ulcers
o Pemphigus Vulgaris

Definition: is a chronic autoimmune, potentially life-threatening, mucocutaneous disease

characterized by intraepithelial blister formation.This results from a breakdown or loss of
intercellular adhesion, thus producing epithelial cell separation known as acantholysis.
Etiology and Pathogenesis
Mechanism responsible for causing the intraepithelial lesion of PV is the binding of circulating
IgG autoantibodies to desmoglein 3, a transmembrane glycoprotein adhesion molecule presents
on desmosomes.This lead to the dissolution or disruption of intercellular junctions and loss of
cell-to-cell adhesion, which known acantholysis.
Progressive acantholysis results in the classic suprabasilar bulla, which involves increasingly
greater areas of epithelium, resulting inloss of large areas of skin and mucosa.
Clinical Features
The classical lesion of pemphigus isa thin-walled bulla arising on otherwise normal skin or
mucosa.The bulla rapidly breaks but continues to extend peripherally, eventually leaving large
areas denuded of skin.
Acharacteristic sign of the disease may be obtained by applicationof pressure to an intact bulla.
In patients with PV, the bullaenlarges by extension to an apparently normal
surface.Anothercharacteristic sign of the disease is that pressure to an apparentlynormal area
results in the formation of a new lesion. This phenomenon, called the Nikolsky sign, results from
the upperlayer of the skin pulling away from the basal layer.
Note: TheNikolskysign is most frequently associated with pemphigus and epidermolysis bullosa.
Some patients with pemphigus develop acute fulminatingdisease, but, in most cases, the disease
develops more slowly, usually taking months to develop to its fullest extent.
Oral Manifestations
Oral lesions usually precede skin involvement by few weeks or months.
Symptoms: pain, bloody or salty taste and excessive salivation.
The oral lesions may begin as the classic bulla on anon-inflamed base; more frequently, the
clinician sees shallowirregular ulcers because the bullae rapidly break.
A thin layer ofepithelium peels away in an irregular pattern, leaving a denudedbase. The edges of
the lesion continue to extend peripherallyover a period of weeks until they involve large portions
of the oralmucosa.

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Most common site is buccal mucosa, often in areas of trauma along the occlusal plane. The
palate andgingiva are other common sites of involvement.
If treatment is institutedduring this time, the disease is easier to control, and the chancefor an
early remission of the disorder is enhanced.
In some cases, the lesions may start as desquamative gingivitis. Itshould be remembered that
desquamative gingivitis is not adiagnosis in itself; these lesions must be biopsied to rule out
thepossibility of PV as well as bullous pemphigoid, mucous membranepemphigoid, and erosive
lichen planus.
Fate: the course of pemphigus is variable where:
1. The disease may result in fluid loss, electrolyte imbalance, septicemia and may terminate
in death in rate of 10% specially in elderly debilitated patients or patients on very high
doses of corticosteroids.
2. Healing is a slow process, without scarring within few weeks, months or years.
Differential diagnosis
- Mucous membrane pemphigoid
- Erythema multiforme,
- Aphthous ulcers.
- Rare syndrome known as paraneoplastic pemphigus:have a lymphoma or other
malignancy and a mucocutaneous pemphigus-like blistering
Diagnosis may be reached through:
a. History of developing painless vesicles that become painful on rupture, with associated
systemic finding of loss of weight, cachexia, anemia and pruritis
b. Clinical examination bullous eruptions on normally looking skin or oral mucosa and
lacking the inflammatory haloes around their margins and +venikolsky’s sign.
c. Special investigations:
1. Direct smear
a) Smear obtained from the vesicular fluid or from recently ruptured vesicle show
acantholytic cells which are isolated.
b) To confirm the diagnosis, use direct immunofluorescent technique to demonstrate a
coating IgG round the acantholytic cells.
2. Biopsy
The specimen should be halved to enable light microscopy and direct immunofluorescent
examination to be carried out.
Fresh bullae (24 hour old) should be excised for biopsy or biopsy is obtained from
perilesional mucosa or skin.

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a. The light microscopy showssuprabasal cleft formation and intraepithelial vesicles

containing free floating acantholytic cells.
b. Immunofluorescentantibody test:
- Indirect immunofluorescent antibody test:
positive reaction in the tissue (honey comb pattern) indicates the presence of
circulating IgG .
- Direct immunofluorescent antibody test:
Positive reaction in the tissue in the form of honey comb pattern indicate the
presence of tissue autoantibodies.
3. Hypoalbuminemia:
Fluid containing albumin escapes from large area of the skin covered by bullae.
4. ES R: is raised
Treatment:
1. 1-2mg / kg body weight (60-100 mg/day) of systemic prednisone to control the signs
and symptoms but later this is reduced to a maintenance dose.
2. High protein diet is indicated especially if the serum albumin is low
3. Topical application of corticosteroids for skin and oral lesions is helpful
4. Antifungal drugs should be used for one week for every 4 weeks of steroid therapy
5. Systemic antibodies may be prescribed to control secondary infection
6. Plasmapheresis
7. Or: High dose iv pulse methyl prednisolone (30 mg/kg body weight) with maximum
dose of 1 gm/ dose on each 3-5 consecutive days. 1gm of the drugs is diluted in 250
ml saline solution and administrated by iv drip method.
This repeated after 21 days. Between the pulse cycles the patient will treat with 40 mg
prednisolone daily if clinical remission occurs, the dose will be reduced gradually.

Dental implications
1. The tissues should be handled with care and undue pressure such as used the mirror
forcibly against the cheek should be avoided. The epithelium is fragile and excess
pressure may cause erosion, although this is less likely to occur in a patient who is well
controlled by corticosteroids.
2. Long term used of steroid can induce adrenal atrophy and adrenal crisis is liable to occur
in dental clinic.
3. Other immunosuppressive drug (azathioprine) may suppress the immune system (T, B
cells and phagocytic cells) as well as bone marrow suppression which can induce anemia,
thrombocytopenia, leukopenia and the patient may suffer wide range of infections

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4. Oral lesions may predate skin eruption in 50-60 % of cases by several months and if the
disease is diagnosed by the dentist and the treatment is started at this time, lots of
advantages are gained:
a. The disease will be easier to control
b. Early remission of the disease is possible
c. The immunosuppressive therapy will be given in low dose and for shorter duration

o Bullous pemphigoid

Definition: is a chronic non-fatal autoimmune disease and characterized by tense, often pruritic
blisters located on the flexor surfaces of the extremities, axilla, groin and lower abdomen.
BP, which is the most common of the subepithelial blistering diseases, occurs chiefly in adults
over the age of 60 years; it isself-limited and may last from a few months to 5 years. It may be a
cause of death in older debilitated individuals
Etiology and Pathogenesis
It is subepithelial blister in the lamina lucida region of the basement membrane. There is no
acantholysis, but the splitin the basement membrane is accompanied by an inflammatory
infiltrate.
Autoantibodies have been demonstrated against basement membrane zone laminin and so-called
bullous pemphigoid antigens, which are found in hemidesmosomes and in the lamina lucida of
basement membrane.
Subsequent to binding of circulating autoantibodies to tissueantigens, a series of events occurs,
one of which is complement activation. This attracts neutrophils andeosinophils to the basement
membrane zone.
These cells then release lysosomal proteases, which inturn participate in degradation of the
basement membrane attachment complex. The final event is tissueseparation at the epithelium-
connective tissue interface.
Clinical Features
The characteristic skin lesion ofBP is a blister on an inflamed base that chiefly involves thescalp,
arms, legs, axilla, and groin. Pruritic maculesand papules may also be a presenting sign.
Unlike pemphigus, BP bullae do not continue to extend at theperiphery to form large denuded
areas.
Oral Manifestations

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Blister may be found in the oral cavity in one third of patients and it is rare on other mucous
membrane.
The oral lesions of pemphigoid are smaller, form moreslowly, and are less painful than those
seen in pemphigusvulgaris, and the extensive labial involvement seen in pemphigusis not
present.
Character of oral lesions appear as tense, discrete blister than rupture leaving relatively painless
non expanding ulcer
Desquamative gingivitis has also beenreported as a manifestation of BP. Early remission of the
oral lesions is more common than those observed in MMP.
Investigations:
Biopsy: is essential to confirm the diagnosis and the diagnosis and the specimen should be
halved to enable light microscopy and direct immunofluorescent examination to be carried out;
a. Light microscopy:
- Typically, intact epithelium is separated along the basement membrane from the
underlying lamina propria forming subepithelial bullae.
- Both acute and chronic infiltrate may be seen in the lamina propria depending on
the stage of the lesion. Lymphocytes and plasma cells dominate the infiltrate of
established lesions.
b. Immunofluorescent examination:
Direct: there is linear deposition of IgG (50-90 %) and C3 (100%) at dermal epidermal
junction.
Indirect: circulating IgG bind to BP antigen in the lamina lucida at the dermal epidermal
junction in 70% of cases.
Treatment
In the mildest and most localized oral lesions apply topical application of potent steroids.
In more generalized oral lesions 60-100 mg prednisone/ day until no new lesions are seen and
then steroid is slowly tapered.
o Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP) is a chronic blistering or vesiculobullous disease that

affects predominantly oral and ocular mucous membranes and other mucosal tissues and less
frequently 20% it affects the skin. It is also known as cicatricial pemphigoid, benign mucous
membrane pemphigoid.
Etiology and Pathogenesis

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The primary lesion of MMP occurs whenautoantibodies directed against proteins in the
basementmembrane zone, acting with complement (C3) and neutrophils, cause a subepithelial
split and subsequent vesicleformation.
Clinical Manifestations
This is a disease of adults and the elderly and tends to affect women more than men. MMP has
rarelybeen reported in children.
The subepithelial lesions of MMP may involve any mucosal surface, but they most
frequentlyinvolve the oral mucosa.
Eyes:The conjunctiva is the second mostcommon site of involvement and can lead to scarring
and adhesions of the canthus (symblepharon).Corneal damage is common, and progressive
scarring leads to blindness in closeto 15% of patients.

Others mucosa: Lesions may also affect the genital mucosa,causing pain and sexual
dysfunction. Laryngeal involvementcauses pain, hoarseness, and difficulty breathing,
whereasesophageal involvement may cause dysphagia, which can leadto debilitation and death in
severe cases.
Skin: usually of the head and neck region and extremities, bullae becomes ulcerated and crusted
and heal by scar.
Oral Manifestations
Oral lesions occur in over 90% of patients with MMP. Desquamative gingivitis is the most
commonmanifestation and may be the only manifestation of thedisease.
Note: Desquamative lesions resemble the lesions of erosive lichen planus and pemphigus, all
cases of desquamative gingivitis should be biopsied and studiedwith both routine histology and
direct immunofluorescenceto determine the correct diagnosis.
Occasionally the oral lesion appears as bullae 10% mainly in gingiva and palate and rarely on
lips and cheeks i.e. opposite to PV. The bullae rupture leaving an ulcer which is: chronic, self-
limiting, shallow slightly painful, non-expanding slowly growing, surrounded by erythematous
zoneand rarely healing by scar.
Course: characterized by remission and exacerbation, however remission is rare. May restricted
to one site (oral) for several years and possibly never develop elsewhere.
Investigations
It is the same as that described for bullous pemphigoid.
1. Histopathologic feature is identical to bullous pemphigoid
2. Immunofluorescent examination:

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Direct: there is linear deposition of IgG and C3 along the basement membrane zone in
80% of cases.
Indirect: circulating IgG bind to MMP antigen located at a lower level of lamina lucida
of the basement membrane at dermal epidermal junction in 10% of cases.
Treatment
1. Asymptomatic disease with gingival involvement:
Oral hygiene reinforcement and frequent scaling and root planning.
2. Symptomatic disease:
- Oral hygiene reinforcement and frequent scaling and root planning if there is
gingival involvement.
- Topical application of potent steroid two to three times a day, this may extend for
long periods of time up to several months to control the disease.
- Intralesional steroid injection may be carried out at a few weeks’ interval.
- Dapsone: as an anti-inflammatory agent
25mg a day for 3days
25mg twice a day for 3days
25mg three times a day for 3 days
50mg twice a day for 1 week
75mg in morning + 25mg at night for I week
75mg in morning + 75mg at night until lesion subsides
- Combination of systemic steroid and immunosuppressive agents
Note: systemic steroid is the last drug to be prescribed for several reasons:
- To avoid the complication of very long term systemic corticosteroid in patient over 50
years old.
- While most inflammatory diseases usually respond to systemic corticosteroid except of
MMP.
- Even high dose of prednisone may produce minimal clinical improvement.

o Erythema Multiforme

Erythema multiforme (EM) is an acute inflammatory diseaseof the skin and mucous membranes
that causes a variety of skin lesions—hence the name “multiforme.”.
EM may occur once or recur, and it shouldbe considered in the diagnosis of multiple acute oral
ulcerswhether or not there is a history of similar lesions. There is alsoa rare chronic form of EM.
Etiology
EM is an immune-mediated disease that may be initiated either by
A. Deposition of immune complexes in the superficial microvasculature (mostly IgM &
C3) of skin and mucosa.

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Many factors are blamed to trigger the immune complexes, but the two major factors are drugs
and infection.
Drugs: oxycam non steroidal anti-inflammatory drugs (NSAIDs); sulfonamides; anticonvulsants
such as carbamazepine, phenobarbital, and phenytoin;trimethoprim-sulfonamide combinations,
allopurinol, andpenicillin.
Infection:herpessimplex virus,Mycoplasma (TB), histoplasmosis, and infectious mononucleosis.
Othertriggers for EM include progesterone,benign andmalignant tumors, radiotherapy, Crohn’s
disease, sarcoidosis.
B. Cell-mediated immunity (herpes associated EM)
Many investigatorsnow believe that the major cause of EM is a cellular immuneresponse to HSV
antigens deposited in keratinocytes of theskin and mucosa.
Note: the majority of patient have no history of recent drug administration or diseases which
may release to the development of EM and so in many cases the etiology is idiopathic.

Clinical manifestations
EM can be classified to:
1. Severe vesiculobullous forms of the disease
a. Stevens-Johnson syndrome
Is characterized by generalized vesicles and bullae involve the skin, mouth, eyes, and
genitals.
Age: is seen most frequently in infants, childrenand young adults, and affects both sexes
equally.
It has an acuteor even an explosive onset; generalized symptoms such as feverand
malaise, anorexia and the patient developsevere vesiculo-bullous lesions.
Skin: involved are the face, neck and trunk, hands, feet, and extensor surfaces of the
elbows and knees.
Typical skin lesions of EM may be nonspecific macules,papules, and vesicles. More
typical skin lesions contain petechiae in the center of the lesion. The
pathognomoniclesion is the target or iris lesion, which consists of a centralbulla or pale
clearing area surrounded by edema and bands oferythema.
Oral:
Symptoms: pain, discomfort, inability to eat, swallowing and increased salivation.
The vesicles develop on erythematous base anywhere in the oral cavity, however the
gingiva is rarely affected.
The vesicles rupture leaving ulcers which are: large deeper, irregular, hemorrhagic ulcer
and surrounded by erythema.

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+ Nikolsky’s sign on inflamed oral mucosa.

Lips show extensively eroded area and large portion of lip mucosa is denuded of
epithelium. The vermillion border gets covered by bloody crusted lesion within few days.
Tongue shows enlargement with indentation and nonspecific ulceration or erosion on the
anterior and lateral border.

b. Toxic epidermal necrolysis (TEN)

Is usually secondary to a drug reaction and results in sloughing of skin and mucosa in
large sheets.
Morbidity, which occurs in 30 to 40% of patients, results fromsecondary infection, fluid
and electrolyte imbalance, or involvementof the lung, liver, or kidneys.
+Nikolsky’s signwith peelingof largearea of the skin leaving painful exudate surface.
So most successfully managed in burn centers,where necrotic skin is removed under
general anesthesia andhealing takes place under sheets of porcine xenografts.
2. Minor form of EM:
The skin and oral mucosa are involved without any systemic manifestation; it is similar
severe form but not as marked as in the sever form.

3. Chronic EM:
It is rare type and it may be seen in immunocompromised patients.

4. Herpes associated EM:

EM may initiate by cell mediated immune reaction to recurrent HSV infection. 20- 40%
of the cases of single episodes of EM and approximately80% of recurrent EM.
Patient who prone to develop EM after recurrent HSV should be placed on prophylactic
maintenance dose of acyclovir to prevent recurrent of herpetic infection, in turn the
development of post herpetic EM is also controlled.
Diagnosis
Made on the total clinical picture including rapid onset of the disease.
1. History
- Sudden onset of vesiculo-bullous lesions on skin/ oral mucous membrane develop
rapidly (1-2) in minor form.
- Sudden onset of fever and vesiculo-bullous lesions develop rapidly (1-2) in sever
form
- Vesiculo-bullous lesions develop 10-14 days after recurrent HSV is herpes
associated EM
2. Clinical examination:
- The character and distribution of oral lesions are fairly typical
- If the skin lesions are present, the diagnosis may be facilitated, thus the skin
should be examined carefully if the oral lesions are suggestive of possible EM.

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3. Special investigation:
- There are no laboratory tests of diagnostic value of EM
- Laboratory procedures are helpful only in excluding other possible disease
Course
- EM has recurrence form, the lesion persists for 2-3 weeks in the minor form and up to 4-6
weeks in sever and chronic form.
- It is self-limiting disease, and the lesions heal with no scar unless there is secondary
infection.
Treatment
Two points have to be considered:
- There is wide range of clinical presentation which vary from mild to severe form.
- The disease self-limiting
a. Mild cases:
Treatment is supportive soft or liquid diet and direct toward elimination of:
- Lesions by topical steroid
- Pain by topical anesthesia
- Infection by tetracycline mouth rinse

b. Moderately severe cases:

- Systemic steroids 30-50 mg prednisone to put the disease under control and then
the dose should be reduced.
- Systemic antibiotic may be indicated to control secondary infection
c. Severe form of EM may need hospital’s admission:
- As feeding may be difficult (pharynx, larynx and esophagus involvement)
- To manage frequent serious complication
- To correct fluid and electrolyte imbalance
- For skin graft which may be needed in TEN
d. Prophylaxis
By use of antiviral drugs is helpful in management of patients with recurrent herpes
associated EM. 400mg acyclovir /day

o Contact Allergic Stomatitis

Pathogenesis and Etiology

Contact allergy results from a delayed hypersensitivity reaction that occurs when antigens of low
molecular weight penetratethe skin or mucosa of susceptible individuals. These antigens
combine with epithelial-derived proteins to form haptens that bind to Langerhans’ cells in the
epithelium.

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The Langerhans’ cells act as antigen presenting cells which present the antigen to T
lymphocytes. After re-exposureto the antigen, sensitized individuals develop an
inflammatoryreaction confined to the site of contact.
Contact stomatitis may result from contact with dentalmaterials, oral hygiene products, or foods.
Common causesof contact oral reactions are cinnamon or peppermint,which are frequently used
flavoring agents in food, candy,and chewing gum, as well as oral hygiene products such
astoothpaste, mouthwash and dental floss.
Dental materials that have been reported to cause cases ofcontact allergic stomatitis include
mercury in amalgam, goldin crowns, free monomer in acrylic, and nickel in orthodonticwire.
Clinical manifestation
The clinical signs and symptoms of contact oral allergy are nonspecific and are frequently
difficult to distinguish fromphysical irritation.
The reaction occurs only at the site of contactand includes a burning sensation or soreness
accompaniedby erythema, and occasionally the formation of vesicles andulcers.
Another oral manifestation of contact allergy is plasma cell gingivitis, which is characterized by
generalized erythemaand edema of the attached gingiva, occasionally accompanied by cheilitis
and glossitis.
The histopathologyis described as sheets of plasma cells that replace normalconnective tissue.
Some cases have been related to an allergenpresent in toothpaste, chewing gum, or candy,
whereasother cases remain of unknown etiology even after extensiveallergy testing.
Plasma cell gingivitis must be distinguishedfrom neoplastic plasma cell diseases such as
plasmacytoma or multiple myeloma.
Diagnosis
Contact allergy is most accurately diagnosed by the use of apatch test.This test is performed by
placing the suspectedallergens in small aluminum disks, which are taped onto hairless portions of
the skin. The disks remain in place for 48 hours. A positive response to a contactallergen is
identified by inflammation at the site of the test, which is graded on a scale of 0 to 3.
Treatment
Management of oral contact allergy depends on the severity ofthe lesions.
- In mild cases, removal of the allergen suffices.
- In more severe symptomatic cases, application of a topical corticosteroid is helpful to
speed healing of painful lesions.

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