immunopathological aspects of oral erythema multiforme

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The immunopathologic mucosal diseases (vesiculobul-lous, vesiculoerosive) as a group present as somewhatcommonly occurring inflammatory mucocutaneouslesions. In the mouth they can appear as erythematousmucosal changes with associated keratoses, ulcerations(erosive areas), desquamation, and occasionally, bullae.Frequently there is accompanying pain, varying frommild discomfort to severe symptoms that can alter sig-nificantly the ability to function. Although external irri-tants aggravate existing lesions, the etiology is on an

idiopathic autoimmune basis.The exact occurrence has not been established

because of an absence of well-designed population-basedstudies, the often cyclical nature, and asymptomaticpatients whose lesions are never diagnosed or recognized.

Diagnosis

The diagnosis is based upon a combination of clinicalcharacteristics and biopsy. At times, immunofluorescentpreparations of biopsied specimens aid in establishing

the classification. These diseases can occur as eitherchronic or cyclical flares, and can appear independentlyor in combination in the mouth, lips, and skin. Othermucosal surfaces are occasionally involved, also.

The most common of these lesions is lichen planus,followed by pemphigoid, erythema multiforme, andpemphigus. Each condition has its own characteristicsboth clinically and microscopically. However, there canbe an overlap of uncertain, confusing clinical changes,as well as a microscopically observed inflammation thatis nonspecific and termed interface mucositis.

Lupus erythematosus and recurrent aphthous stom-atitis are considered here, because both are immuno-pathologic conditions, and sometimes they are a con-fusing factor in the differential diagnosis.

Pathologic and molecular

correlates of disease

Lichen planus

Lichen planus (LP) is a fairly common immunopatho-logic mucocutaneous disorder that is mediated by a T-

Figure 211 Histology of lichen planus. A band of lymphocytes, all of

which immunolabel as T cells (both CD4 and CD8), infiltrates the

epithelialconnective tissue interface.

Diagnosis, 206

Pathologic and molecular correlates

of disease, 206

Lichen planus, 206

Erythema multiforme, 208

Mucous membrane pemphigoid, 208

Pemphigus vulgaris, 209

Lupus erythematosus, 210

Recurrent aphthous stomatitis, 210

Clinical characteristics, 210

Treatment, 213

Suggested reading, 217

21ImmunopathologicMucosal LesionsSol Silverman, Jr, MA, DDS, and L. Roy Eversole, DDS, MSD, MA


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I M M U N O P A T H O L O G I C M U C O S A L L E S I O N S 207

lymphocyte reaction to antigenic stimuli residing in theepithelial layer (Figure 211). Immunomarker studieshave disclosed that the lymphocyte population is exclu-sively T-cell in nature with a mixture of CD4 and CD8lymphocytes that express integrin molecules of the 1Class (Figure 212). These integrin ligands bind to

other adhesion molecules that are upregulated onendothelial cells (vascular cell adhesion molecule[VCAM]) and epithelial cells (intracellular adhesionmolecules [ICAM]). Lower strata keratinocytes, whichalso express major histocompatibility complex class II(MHC-II) molecules (human leukocyte antigen-D/DR[HLA D/DR]) in lichen planus, are able to present anti-gens to cells bearing the CD4-associated T-cell receptor.CD8 lymphocytes are able to bind to antigen-com-plexed MHC-I molecules on keratinoctyes.

The basement membrane is altered in LP, and in thisregion, excessive amounts of fibrinogen are deposited, afeature with diagnostic value when direct immunfluores-

cence is applied (Figure 213, A). Other basement mem-brane molecules, such as fibronectin, laminin, and typesIV and VII collagens are upregulated. Angiogenesis andvasodilation are considerably increased in lesional sub-mucosa. In the inflamed epithelium, lower strata kera-tinocytes express and secrete chemokines that are chemo-tactic to lymphocytes. Thus, following antigenicchallenge, lymphocytes adhere to vascular endothelia,

Figure 212 The afferent limb of immunoreactivity in lichen planus.

Antigenic challenge comes from the external environment or may be

the result of keratinocyte autoantigen expression. Dendritic Langerhans

cells and antigen-bearing class II molecules on keratinocytes relay mol-

ecular information to reactive CD4 cells in the regional lymph nodes,

which engender an effector T helper cell (Th1) pathway response. MHC

= major histocompatibility complex; Ag = antigen.

Figure 213 Immunoflourescent patterns in bullous or desqua-

mative oral lesions: A, sub-basement membrane deposition of

fibrinogen in lichen planus; B, perivascular complement fraction 3

localization in erythema multiforme; C, basement membrane IgG

deposition in mucous membrane pemphigoid; and D, pericellular,

desmosomal localization of IgG in pemphigus vulgaris.

Lymph node

Th1 response

CD4CD8

Langerhanscell

MHCAg

Ag

Ag

D

C

B

A


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208 C H A P T E R 2 1

allergenic challenging agent is the reaction to cinnamon.Clinically, the lesions are lichenoid, as they are histo-logically, manifesting a unique and characteristicperivascular lymphoid infiltrate in the submucosa.Lastly, with regard to pathogenesis, topically and sys-temically administered medications may cause a

lichenoid drug reaction of skin and mucosa.

Erythema multiforme

Erythema multiforme (EM), a mucocutaneous inflam-matory reaction, arises as a consequence of immunecomplex mechanisms. Although some cases are ofunknown origin, the majority are sequelae to drugadministration, usually sulfa drugs (both antibiotic sul-fas and hypoglycemic sulfonylureas), or in some caseseven represent postherpetic immune complex phenom-ena. In oral mucosal EM, herpes simplex virus (HSV)allergenicity is an uncommon associated factor. Further-more, causative agents (antigens) are rarely identified inoral EM. However, in both cases, antigenic peptidesform complexes with IgG complement-fixing immuno-globulins, and these complexes filter out into vesselwalls, where they bind complement and initiate a leuko-cytic infiltrate, consisting of neutrophils and macro-phages (Figure 213, B). These leukocytes release oxy-gen free radical species and lytic enzymes that culminatein necrosis of the epithelium, which results in bulla anddiffuse desquamation (Figure 215). Some investigatorshave identified viral antigens and even viral DNA in EMlesions, yet no active infectious organisms are extant.

Mucous membrane pemphigoid

The mucous membrane pemphigoid (MMP) phenotypeis the consequence of autoimmune humoral disease. Theantigenic targets that become immunogens reside withinthe basement membrane adhesion complex (BMAC).Immunologic reactions in this region dissociate adhe-sion molecules, resulting in sub-basilar cells. The basalcells attach to this membrane via extracellular integrinsand collagens, which bind ligands in the lamina lucida.These ligands include laminins 1, 5, and 6, which in

turn extend into the lamina densa where they bind typeIV collagen. The lamina densa is bound to the connec-tive tissue collagens (types I and II) by anchoring fibrilscomprised of type VII collagen (Figure 216). In bullouspemphigoid (BP) of skin, both BP antigen BP230 andcollagen XII are the antigenic targets, which are boundby autoreactive complement-fixing IgG or IgM. Com-plement-binding to the BMAC stimulates leukocyteinfiltration of the submucosa whereby neutrophils andmacrophages may directly damage and dissociate theadhesion molecules.

emigrate into the submucosa, and migrate under theinfluence of the epithelial secreted chemoattractant mole-cules. Lymphocytes are then able to adhere to extracellu-lar matrix (ECM) molecules that are overproduced alongthe basement membrane. Upon crossing the epithelialmesenchymal interface, ECM molecules are able to bind,

via integrins, to cell-surface adhesion molecules patho-logically expressed on keratinocytes (Figure 214).Therefore, LP is a T-cell mediated immunologic

mucosal and cutaneous disease and, as such, it respondsto T-cell immunosuppressive drugs. As previously alludedto, the antigenic agent responsible for this reaction hasremained elusive in most cases. This has prompted someinvestigators to propose an autoimmune pathogenesis.

Lichenoid is a term used to describe lesions that clin-ically and histologically can resemble LP. As an exam-ple, and although rare, some instances of LP-like lesionsare found adjacent to corroding dental amalgams, andsuch lesions are referred to as contact lichenoid lesions.

When such an association occurs, these lichenoidlesions resolve after removal of the adjacent amalgam.Both clinical and laboratory studies have showndelayed-type hypersensitivity to dental metals, particu-larly mercury. Another lichenoid process with a known

Figure 214 The efferent limb of immunoreactivity in lichen planus.

Reactive T cells leave submucosal vessels and enter the connective tis-

sues. Chemokines from keratinocytes direct lymphocyte traffic along

extracellular matrix using cellmatrix adhesion molecules. Cytotoxic T

cells release perforin and other enzymes, which lyse basal cells, particu-

larly in the erosive form of the disease. CAMS = cell adhesion molecules;

CD4 = helper inducer T cells; CD8 = cytotoxic T cells; CTL = cytotoxic T

lymphocyte; HLA-DR = human leukocyte antigen class II antigen pre-

sentation molecules; IFN-= interferon gamma; IL = interleukin; MCP =

monocyte chemoattractant protein; TCR = T-cell antigen receptor; VLA

= very late activation.

Keratinocytes

express

HLA-DR

CAMs

Integrins

Keratinocytes

CytokinesIFN-, IL

Chemokines

MCP

Perforin

CD4

CD8

CTL

TCR

Thick basement membrane

Fibrinogen

VLA

Extracellular Matrix


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There are other antigenic targets in variants ofMMP. Therefore, pemphigoid is a specific phenotypewith sub-basilar cell separation and deposition ofBMAC immunoreactants (Figure 213, C), character-ized by a heterogeneous group of antigenic targetsunique to the basement membrane. In linear IgA dis-ease, a specific antigenic target resides in the laminalucida. In antiepiligrin cicatricial pemphigoid, the targetantigen is laminin-5 (epiligrin). It is noteworthy thatthese same adhesion molecules can be mutated in the

inherited collective group of bullous diseases known asepidermolysis bullosa (EB). Oral lesions do in fact occurin the genetic forms of EB, and in one genotypic form,ameloblasts are damaged, with resultant enamel pittingand hypoplasia (see Clinical characteristics).

Pemphigus vulgaris

Pemphigus vulgaris (PV) is a disease that involves IgGand sometimes IgA and IgM autoantibodies directed tothe intercellular desmosomal adhesion molecule

desmoglein III. This molecule mediates cellcell adhe-sion between contiguous keratinocytes, and when anti-bodies bind, they sterically interfere with the ability ofthe desmogleins to adhere to one another. The result isa suprabasilar clefting with acantholysis and a pericel-lular or desmosomal distribution of immunoreactants(Figure 213, D;Figure 217). There are some drugs,such as captopril and penicillamine, that possesssulfhydryl groups that can induce the formation of PVantibodies to desmoglein, a process that is reversibleonce the drug is withdrawn.

Paraneoplastic pemphigus is a disease characterizedby mucocutaneous bullae and ulcerations with apredilection for the lips and conjuntiva. These patientsharbor an underlying neoplasm, usually lymphoma.Both suprabasilar clefting and lichenoid histologic pre-sentations are seen. These patients have autoantibodiesthat target the desmoplakins, plaque proteins of thedesmosome that are independent from desmoglein. Apositive pericellular distribution of immunoreactants canbe seen with indirect immunofluorescence using patientserum and urinary bladder epithelium as a substrate.

Keratinocyte

necrosis

Immune

complexes

complement

Polymorphonuclear

macrophages

Figure 215 Pathogenesis of immune complex vasculitis in erythema

multifome. Immune complexes settle in vessel walls where complement

fixation occurs and promulgates an inflammatory reaction with leuko-

cyte trafficking into the submucosa and epithelium. Vasculitis may also

contribute to ischemic necrosis of the overlying epithelium.

Figure 216 The hemidesmosome basement membrane adhesion

complex: basement membrane antigens and the pemphigoid pheno-

type. Numerous chemical species are involved in the adhesion of basal

cells to the basement membrane. These adhesion molecules may

become antigenic targets for IgG, and IgM complement-fixing antibod-

ies as well as IgA.

IgG, IgA, IgM

Complement

Lamina lucidaLamina densa

DesmogleinAg

IgG,IgA,IgM

complement

Tzanckcell

DGDP

CK PG

Figure 217 Desmoglein is the antigenic target in pemphigus vul-

garis. Antidesmoglein antibodies sterically interfere with the inter-

action of adhesion proteins with similar molecules on neighboring cell

desmosomes. CK = cytokeratin; DG = desmoglein; DP = desmoplakin;

PG = plakoglobin.


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210 C H A P T E R 2 1

Lupus erythematosus

Lupus erythematosus (LE) is an autoimmune disease thatis characterized by the presence of serum circulating anti-bodies directed against cell nucleus components. Anti-nuclear antibodies (ANA) are of major diagnostic impor-tance in LE and include anti-DNA, antihistone,antiribonuclear, and antinucleolar antibodies. In addi-tion, antibody directed toward basement membranes isdemonstrable using direct immunofluorescent staining,generating the so-called lupus band test, which showsIgG and IgM localization along the skin and oral mucosalbasement membranes. Immunoreactants are also local-ized to glomerular basement membranes in systemiclupus. Many other antibodies are found in lupus, whichis now considered to be a dysregulation of immune toler-ance to self antigens. These various autoantibodies formimmune complexes, which are pathogenic and respon-sible for vascular and renal lesions seen in the disease.

Recurrent aphthous stomatitis

The earliest lesion of recurrent aphthous stomatitis is apreulcerative inflammatory focus within the oral epithe-lium that is characterized by an influx of T lympho-cytes. Cytotoxic T cells appear to be directed to someantigenic determinant located on or within keratino-cytes (Figure 218). The release of various immuno-reactive cytokines and chemokines induces a cell-mediated response that is believed to result inkeratinocyte lysis. Many studies have demonstratedboth antibody and T cell-mediated immunologic reac-tions with oral keratinocytes; however, the antigenremains unidentified and could be a hapten, a virus, oran allergen. The antigenic stimulus, whatever it may be,is short-lived and focal, since the lesions are separatedby unaffected mucosa and last only 10 to 14 days.

Clinical characteristics

Lichen planus (LP) has a reticular form (reticular surfacekeratoses), an atrophic form (erythematous mucosaalternating with keratoses), and the erosive form (com-bination of ulcerations, erythematous mucosa, and ker-

atosis) (Figure 219). The reticular form is characterizedby lacey interconnecting stria of Wickham that occurtypically on the buccal mucosa with extention into themandibular vestibule, and such lesions are usually with-out symptoms. Gingival involvement is common, partic-ularly in the erosive form, where it may present asdesquamative gingivitis (a descriptive clinical term) withinterspersed foci of keratosis. Over time, patients mayexhibit all three forms of the disease and, therefore,show longitudinal variation in the manifestation ofsymptoms, since usually, only the atrophic and erosiveforms are painful. Oral LP usually appears in midlife andis more common among females; it rarely occurs in chil-

dren or even adolescents. Unusual presentations includea papular variant of the keratotic reticular form and apigmented form in which white and red lesions can beassociated with brown or black diffuse melanosis. Theprimary microscopic feature is hyperkeratosis combinedwith subepithelial white cell (mainly lymphocytic) infil-trate. Often there is deterioration of the basement mem-brane and irregular epithelial hyperplasia.

Pemphigoid can occur in a cicatricial or bullousform. The former is most common, and it most oftenoccurs on mucosal surfaces. Clinically, it may present asan erythematous mucosal surface, and frequently, thereare associated areas of pseudomembrane-covered ero-

sive lesions stemming from ruptured vesicles (Figure2110). The most common site is the gingiva, where thelesions may present as a desquamative gingivitis. Otheroral mucosal sites may be involved with or without gin-gival manifestations. Occasionally there is eye involve-ment, with scar tissue forming between the lower eye lidand the conjunctiva (symblepharon). There is a markedfemale predilection, and the lesions usually appear inmid- to late life.

Erythema multiforme is a hypersensitivity reactionthat can occur as a mild to severe reaction. In mucosalerythema multiforme, an offending antigen cannot

always be identified. The lesions may occur indepen-dently or in combination in the mouth, lips, and skin.They appear as nonspecific erythematous lesions andoften as ulcerations that are irregular in appearance(Figure 2111). Whereas any mucosal tissues can beinvolved, crusting ulcerations of the lips are often pre-sent. Multiple mucosal sites can be involved, and onset,whether for a chronic or cyclical form, is usually acute.When a triggering event can be identified, it is usually asulfa drug (antibiotic and hypoglycemic). Erythemamultiforme can be seen in either gender and at any age.

Figure 218 The pathogenesis of recurrent aphthous stomatitis

involves T cell infiltration to antigenic targets in the surface epithelium.

Keratinocyte

necrosis

CytotoxicT cells

Perforin

Fibrin clot

Keratinocyte

and lymphocyte

inflammatory

cytokines

chemokines

Ag ?


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Figure 219 Lichen planus (LP) forms. A, Classic appearance of skin-involved LP. About 20% of patients with oral LP have a history or active skin

lesions. B, Reticular LP occurring on the vermilion border of the lip. C, Classic reticular LP. D, Punctate LP that could be confused with leukoplakia,

frictional keratosis, or candidiasis. E, A common site of atrophic LP in the posterior mandibular buccogingival reflex. It is usually bilateral. F, Erosive

LP of the buccal mucosa. G, Erosive LP of the palate. H, Erosive LP of the tongue dorsum.

A

C

E

G

B

D

F

H


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212 C H A P T E R 2 1

Pemphigus in the mouth is fairly uncommon but mayoccur prior to skin involvement; rarely, only oral lesionsare present. The ulcerations of pemphigus are usuallysomewhat characteristic because of their irregular andcavernous appearance (Figure 2112). There is often con-siderable associated pain. These ulcerations can occur

anywhere in the mouth, with a common location beingthe pillar of fauces-soft palate region. The patients areusually adults, with both genders being equally affected.

Lesions of lupus erythematosus (LE), whether dis-coid or systemic, are rarely found in the mouth. Whenpresent, they can appear as nonspecific, chronic, red-white, erosive lesions (Figure 2113). The diagnosis isbased upon clinical suspicion, confirmation of LEinvolving skin or other organ systems, and suggestivemicroscopic findings.

Recurrent aphthous stomatitis (RAS) most typicallypresents as characteristic shallow single or multipleulcerations with surrounding inflammatory halos (Fig-

ure 2114). It recurs at varying intervals based uponpatient differences and a variety of initiating physicaland chemical factors. Almost always, RAS occurs onnonkeratinizing oral epithelium (buccal and labialmucosae, lateral and ventral tongue, floor of the mouth,

and soft palate). The diagnosis is usually supported bya history of recurrence, pain, and spontaneous healing.Whereas certain foods and local trauma can initiatethese ulcers, the prime etiology appears to be based onlymphocytes that are chemotactically attracted to thesevarious sites, which in turn pathologically react with

epithelium. Before an ulcer becomes apparent, patientscan often sense an aura of discomfort. Duration of RASusually does not exceed 1 to 2 weeks.

Usually, RAS lesions do not exceed 5 mm, but theycan be multiple. Sometimes, the clustering and irregu-larity in size almost suggests a hypersensitivity reaction(EM). When RAS ulcers exceed 6 mm, they are desig-nated as major aphthae. This indicates a deeper inflam-matory infiltrate, a longer duration, and increased pain.In immunocompromised patients, major aphthae can beconfused with granulomatous or malignant lesions. Ifthe diagnosis is indefinite or an ulcer persists, a biopsyis indicated. When RAS lesions are associated with gen-

ital or eye lesions, arthritis, or dermatologic pathoses(ie, erythema nodosum), the condition is termedBehets syndrome.

Epidermolysis bullosa is an incurable symptomcomplex, with the main oral finding being mucosal

Figure 2110 Mucous membrane pemphigoid (MMP). A, MMP most frequently occurs on the gingiva and appears as marked erythema. This pre-

sentation is often referred to as desquamative gingivitis. B, Ulcerative MMP of the gingiva. Note pseudomembrane-covered erosive areas from col-

lapsed vesicles. C, Buccal involvement of MMP. D, A symblepharon occurring in a patient with oral lesions of MMP.

A

C

B

D


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ulcerations that can vary from epithelial friability caus-ing moderate dysfunction to life-threatening bullae.

With all these lesions, the differential diagnosis is ofutmost importance. First, since these are chronic orrecurring incurable immunologic diseases, patients andtheir primary care physicians desire an exact classifica-

tion. In turn, this is necessary to justify the regimens oftoxic drugs often required to control the symptoms andsigns. It should always be kept in mind that dysplastic,or even malignant lesions, can resemble some of theclinical presentations, and this must be ruled out in theinitial diagnosis as well as in follow-up.

Treatment

Since these diseases are chronic and incurable, manage-ment is focused upon the severity of symptoms and thepatients general health. The approach is to neutralizeoffending lymphocytes that do not recognize some host

cells, releasing cytokines that initiate the inflammatoryresponse and the signs and symptoms. Assurance thatthese are not infectious (contagious) diseases, and rulingout malignancy are both important components ofmanagement and patient care.

Systemically, the most useful drug to control the dam-aging lymphocyte response is prednisone. Usually 40 to80 mg daily reduces signs and symptoms; if it is taken for

A

C

B

D

E

Figure 2111 Erythema multiforme (EM). A, Classic bulls-eye lesion

of EM involving skin. B, Acute EM of the lips present for 1 week. No

antigen could be identified. The lesion responded to a combination of

prednisone and azathioprine. C, EM involving the buccal mucosa.D, EM

involving the palate. E, EM of the anterior tongue manifested by ery-

thema, loss of filiform papillae, and burning pain. The spontaneous

signs and symptoms, present for 2 weeks, disappeared after a 3-day

course of systemic prednisone.


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214 C H A P T E R 2 1

less than 2 weeks tapering is unnecessary. The philosophyof treatment is high dose, short course. This minimizesthe adverse side effects of longer-term therapy that mightbe necessary with a lower dose. If an increased dosage ortime is required, then tapering is in order (Figures 2115to 2117). The most common side effects from short-

term administration of prednisone are insomnia, moodalterations, and fluid retention (bloating).Care also must be taken in patients with certain sys-

temic diseases. Prednisone converts liver and muscleglycogen to glucose, thereby putting diabetic patients atrisk from hyperglycemia. Because of fluid retentionfrom decreased sodium elimination, hypertension maycreate a problem. Potassium diuresis is a small problem,but can be accentuated in patients taking diuretics. This

can interfere with muscle function. Caution must alsobe taken in patients with a history of gastrointestinalulcers, to avoid the possibility of promoting ulcer bleed-ing. Because of possible changes in ocular pressure,patients with glaucoma should be cleared before usage.Long-term administration of prednisone can complicate

osteoporosis, because of calcium loss from bone andlack of replacement.Sometimes, combining the cytotoxic (antimetabo-

lite) drug azathioprine (Imuran) with prednisone syner-gistically enhances the anti-inflammatory effect. Theusual effective daily supplemental dose when neededvaries between 50 and 100 mg daily. At times, when apatient is intolerant to the prednisone dosage necessaryto control signs and symptoms, a lower dose of pred-

C

B

A

C

B

A

Figure 2112 Pemphigus vulgaris (PV). A, PV of the buccal mucosa.

The patient also had skin lesions. B, PV of the palate. The buccal mucosa

were also involved. C, PV of the tongue in a patient who had skin in-

volement that occurred after the oral lesions appeared.

Figure 2113 Lupus erythematosus (LE). A, Typical oral manifestation

of LE on the buccal mucosa in a patient with the discoid form. (LE

lesions can sometimes be confused with lichen planus.) B, Skin lesions of

LE, seen in the same patient. C, An advanced palatal lesion of LE in a

patient with systemic LE.


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nisone can be made effective by adding azathioprine.The combination is also considered in patients withacutely severe inflammatory signs and symptoms.

Topical agents are used when there are medical rea-sons not to use systemic medication or if the patient haspersonal objections. In addition, topicals may be prefer-

able for patients with mild disease. When used, the cor-ticosteroids must be those with high potency, otherwisethey are not effective. The corticosteroids that currentlyhave shown topical efficacy are fluorinated (whichincreases the half-life and potency) and include fluocin-onide (Lidex), clobetasol (Temovate), and halobetasol(Ultravate). They are all 0.05% and can be used as a gel,or the ointment form can be mixed with equal partsorabase as a paste. They can be applied up to threetimes daily, with long-term studies showing no adverseside effects (Figures 2118 and 2119). Mouthrinses

A

B

C

Figure 2114 Recurrent aphthous stomatitis (RAS). A, Typical minor

RAS in unkeratinized mucosa of the tongue. B, Major RAS of the soft

palate. The patient would have about four attacks a year, without any

evident initiating factor. C, Multiple RAS of unknown etiology. The

attacks were almost constant, with only 2 to 3 weeks between flares.

A

B

Figure 2115 A, Painful mucous membrane pemphigoid present for

more than 1 year. B, One week after daily oral intake of 80 mg of pred-

nisone and 100 mg of azathioprine the signs and symptoms dramatically

regressed. There were no adverse side effects, and the drugs were

slowly tapered.

A

B

Figure 2116 A, Erythema multiforme of unknown etiology present for

4 months. B, 60 mg of prednisone daily for 1 week led to remission. The

patient would have occasional recurrences managed in the same manner.


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216 C H A P T E R 2 1

A

B

A

BFigure 2118 A, Painful erosive lichen planus of the gingiva present

for 3 years. The patient preferred not to use systemic medication, if pos-

sible. B, After 2 weeks of fluocinonide ointment mixed with equal parts

orabase applied three to five times daily, there was marked regression.

The patient is now maintained with lower daily applications.

Figure 2119 Painful mucous membrane pemphigoid present for 1

year. After 3 weeks of daily applications of fluocinonide paste (0.05%

Lidex ointment mixed with equal parts orabase), there was control of

the signs and symptoms.

also may be helpful. The one with which we have expe-rience is elixir of dexamethasone, 0.5 mg/5mL (1 tea-spoonful held in the mouth for up to 3 minutes, thenspit out) used up to four times daily. No rinsing or eat-ing for half an hour afterward is advised to have maxi-mum tissue and lesion contact.

Sometimes the use of either systemic or topical cor-ticosteroids causes a flare of candidal overgrowth (can-didiasis). This is based upon the ability of these drugs toconvert glycogen to glucose, leading to increased sub-strate upon which these yeasts (fungi) can feed, repli-cate, and infect. Topical or systemic antifungal medica-tion can control this somewhat infrequent complication(see Chapter 18). Studies with the use of dapsone,thalidomide, cyclosporine, and levamisole to reduce thecausative immunologic activity have been inconclusive.These treatments also incur risks of side effects and con-siderable expense.

In conclusion, a differential diagnosis of mucosal

lesions must be established, the patient must be orientedto the chronic and benign nature of these diseases, andtreatment must be symptom-specific. The patients med-ical provider must be involved, so that there is a teamapproach to disease management. It is important to fol-low these patients periodically to reinforce the percep-tion of chronicity, to manage flares, and to examine for

Figure 2117 Pemphigus vulgaris present on the gingiva for 7

months, without any skin involvement. One week after 80 mg pred-

nisone daily there was complete control. The patient was then main-

tained on topical corticosteroids.

A

B


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Lozada-Nur F, Miranda C. Oral lichen planus: topical and sys-

temic therapy. Semin Cutan Med Surg 1997;16:295300.

Lozada-Nur F, Shillitoe EJ. Erythema multiforme and herpes

simplex virus. J Dent Res 1985;64:93031.

Mobini N, Nagarwalla N, Ahmed R. Oral pemphigoid. Sub-

set of cicatricial pemphigoid? Oral Surg Oral Med Oral

Pathol Oral Radiol Endod 1998;85:3743.Porter SR, Kirby A, Olsen I, Barrett W. Immunologic aspects

of dermal and oral lichen planus: a review. Oral Surg Oral

Med Oral Pathol Oral Radiol Endod 1997;83:35866.

Rojo-Morena JL, Bagan JV, Rojo-Moreno J, et al. Psychologic

factors and oral lichen planus. Oral Surg Oral Med Oral

Pathol Oral Radiol Endod 1998;86:68791.

Scully C, Carrozzo M, Gandolfo S, et al. Update on mucous

membrane pemphigoid. A heterogeneous immune-medi-

ated subepithelial blistering entity. Oral Surg Oral Med

Oral Pathol Oral Radiol Endod 1999;88:5668.

Ship JA. Recurrent aphthous stomatitis: an update. Oral Surg

Oral Med Oral Pathol Oral Radiol Endod 1996;81:1417.

Silverman S Jr, Bahl S. Oral lichen planus update: clinicalcharacteristics, treatment responses, and malignant trans-

formation in 95 patients. Am J Dent 1997;10:25963.

Silverman S Jr, Gorsky M, Lozada-Nur F, Giannotti K. A

prospective study of findings and management in 214

patients with oral lichen planus. Oral Surg Oral Med Oral

Pathol Oral Radiol Endod 1991;72:66570.

Silverman S Jr, Lozada-Nur F, Migliorati C. Clinical efficacy

of prednisone in the treatment of patients with oral

inflammatory ulcerative diseases: a study of 55 patients.

Oral Surg 1985;59:3605.

Snow JL, Gibson LE. A pharmacogenetic basis for the safe

and effective use of azathioprine and other thiopurine

drugs in dermatologic patients. J Am Acad Dermatol1995;32:11416.

Vincent SD, Lilly GE, Baker KA. Clinical, historic, and thera-

peutic features of cicatricial pemphigoid. A literature

review and open therapeutic trial with corticosteroids.

Oral Surg Oral Med Oral Pathol 1993;76:4539.

Weinberg MA, Insler MS, Campen RB. Mucocutaneous fea-

tures of autoimmune blistering diseases. Oral Surg Oral

Med Oral Pathol Oral Radiol Endod 1997;84:51734.

Wood AJJ. Management of acquired bullous skin diseases. N

Engl J Med 1995;333:147584.

the possibility of additional tissue changes. Follow-up isespecially significant in oral LP, since there is a risk thata small number of LP patients (approximately 2%) maydevelop an oral squamous cell carcinoma over time.

Suggested reading

Anhault GJ, Kim S, Stanley JR. Paraneoplastic pemphigus: an

autoimmune mucocutaneous disease associated with neo-

plasia. N Engl J Med 1990;323:172935.

Chainani-Wu N, Silverman S Jr, Lozada-Nur F, et al. Oral

lichen planus: patient profile, disease progression and

treatment responses. J Am Dent Assoc 2001;132:9019.

Dabelsteen E. Molecular biological aspects of acquired bul-

lous diseases. Crit Rev Oral Biol Med 1998;9:16278.

De Rossi SS, Glick M. Lupus erythematosus: considerations

for dentistry. J Am Dent Assoc 1998;129:33039.

Eversole LR. Oral mucosal diseases. In: Millar HD, Mason

DK, eds. 2nd World Workshop on Oral Medicine. AnnArbor: University of Michigan, 1993.

Eversole LR. Immunopathology of oral mucosal ulcerative,

desquamative, and bullous diseases. Selective review of the

literature. Oral Surg Oral Med Oral Pathol 1994;77:

55571.

Eversole LR. Immunopathogenesis of oral lichen planus and

recurrent aphthous stomatitis. Semin Cutan Med Surg

1997;16:28494.

Flier JS, Underhill LH. The hypothalamic-pituitary-adrenal

axis and immune-mediated inflammation. N Engl J Med

1995;332:135160.

Jonsson R, Mountz J, Koopman W. Elucidating the pathogen-

esis of autoimmune disease: recent advances at the molec-ular level and relevance to oral mucosal disease. J Oral

Pathol Med 1990;19:34150.

Lamey PJ, Rees TD, Binnie WH, Rankin KV. Mucous mem-

brane pemphigoid. Treatment experience at two institu-

tions. Oral Surg Oral Med Oral Pathol 1992;74:503.

Lozada-Nur F, Miranda C, Maliski R. Double-blind clinical

trial of 0.05% clobetasol propionate ointment in orabase

and 0.05% fluocinonide ointment in orabase in the treat-

ment of patients with oral vesiculoerosive diseases. Oral

Surg Oral Med Oral Pathol 1994;77:598604.

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