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Australian Dental Journal 2010; 55:(1 Suppl): 2338

doi: 10.1111/j.1834-7819.2010.01196.x

Oral mucosal diseases: the inflammatory dermatoses

M Schifter,* S-C Yeoh, H Coleman,* A Georgiou*

*Oral MedicineOral Pathology Unit, Westmead Centre for Oral Health, Westmead Hospital, Sydney.Oral MedicineOral Pathology, Liverpool and Royal Prince Alfred Hospitals and The Sydney Dental Hospital, Sydney.

ABSTRACT

The oral inflammatory dermatoses is a term used to describe a number of predominantly immune-mediated disorders: lichenplanus (LP), erythema multiforme (EM), the vesiculobullous diseases pemphigoid (MMP), pemphigus (PV) andepidermolysis bullosa acquisita (EBA). These conditions are characterized by frequent involvement of the oral mucosaand often associated with extraoral manifestations, particularly of the skin, but can involve the eyes, both the conjunctivaand sclera, the nasal and pharyngeal mucosa, as well as the genitals. Given their frequent, and sometimes initial involvementof the oral mucosa, oral health professionals need to be both familiar with the clinical features and presentations of theseconditions, and appreciate their critical role in management.

This paper reviews the clinical features and presentation of the oral dermatoses, provides guidance as to the appropriateinvestigations needed to differentiate and correctly diagnose these conditions, details the aetio-pathology of these diseasesand discusses their management.

Keywords: Autoimmune, blister, bullae, corticosteroids, dermatoses, desquamative, erosion, immune-mediated, immunosuppression,steroid-sparing, vesicles, vesiculobullous, ulcers.

Abbreviations and acronyms: ADCC = antibody dependent cellular cytotoxicity; BMZ = basement membrane zone; CDC = complementdependent cytotoxicity; cGVHD = chronic graft-versus-host disease; DIF = direct immuno-fluorescence; DLE = discoid lupuserythematosus; EB = epidermolysis bullosa; EBA = epidermolysis bullosa acquisita; EM = erythema multiforme; c-IFN = gamma-interferon; MMP = mucous membrane pemphigoid; OCP = ocular cicatricial pemphigoid; OLCL = oral lichenoid contact lesions; OLDR =

oral lichenoid drug reactions; OLP = oral lichen planus; OMMP = oral mucous membrane pemphigoid; PUVA = psoralen ultraviolet A light;PV = pemphigus vulgaris; SJS = Stevens Johnson syndrome; TEN = toxic epidermal necrolysis; TNF-a = tumour necrosis factor alpha.

ORAL LICHEN PLANUS

Lichen planus is a chronic systemic disease of estab-lished immune-mediated pathogenesis.1 It most com-monly, and most protractedly, involves the mucosa ofthe oral cavity, hence it is of interest and concern to

dentists, but it can involve other sites, namely the skin,the scalp (with inflammation around and affecting thehair follicles resulting in alopecia), the nails as well asthe genital area the vulval and vaginal mucosa, andthe glans penis. There are six recognized oral presen-tations of lichen planus: (1) reticular; (2) papular; and(3) plaque-form; and the (4) atrophic; (5) ulcerative(erosive) and rare (6) bullous form. These latter threeforms can be associated with significant discomfortrequiring either topical andor systemic immunosup-pressive therapy.2

The cause(s) of the various oral lichenoid lesions,ranging from idiopathic oral lichen planus (OLP) to the

contact lesion, is not understood, but all the lesionsare characterized histologically by a typical lichenoidtissue reaction featuring a band-like lymphohistiocyticinfiltrate within the lamina propria and liquefactiondegeneration of the basal keratinocytes. These reactionsmay be the result of several diverse possible triggers,

but all culminate in a common pathologic process, thatof T-lymphocyte directed, immune-mediated, damageto the oral epithelial basal cells.1,2

Epidemiology

OLP is a common condition. To date there have beenno studies of the prevalence of OLP in Australia.Overseas data from comparable countries indicate aprevalence of between 0.5 to 2.2% of the population.2

However, OLP most frequently presents in women, bya ratio of approximately 3:1 to 3:2 compared with men,aged 40 years and above.

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MANAGEMENT

Diagnosis

The diagnosis of OLP is usually made on clinicalfeatures alone. However, careful attention to the

clinical history is essential, to ensure assessment, andif warranted, the appropriate management, of theextraoral manifestations of lichen planus.1

The signs and symptoms canvary considerably. Lichenplanus of the oral mucosa occurs most often in theabsence of skin lesions. Symptomatically, OLP can alsovary, with patients presenting with complaints of mildbut noticeable intolerance to particularly salty, spicy oracidic foods (such as any form of curry). Rarely, patientswill present with widespread oral mucosal ulcerationthat is spontaneously very painful and so elicit theirpresentation. The reticular, papular, and plaque forms ofOLP are often asymptomatic, and are often detected

coincidentally by the dentist. Given the concern aboutthe potential for OLP to undergo malignant transforma-tion,1,35 and the critical role of the dentist in oral cancerdetection, opportunistic screening by dentists for allforms of oral mucosal disease is strongly encouraged.

Mucosal lesions are usually multiple and almostalways have a bilateral, symmetrical distribution. Theycommonly take the form of minute white papules thatgradually enlarge and coalesce to form either a reticular,annular, or plaque-like pattern. A characteristic featureis the presence of slender white lines (Wickhams striae)radiating from the papules. In the reticular form, there is

a lace-like network of slightly raised white lines, ofteninterspersed with papules or rings (Fig 1). The plaque-like form may be difficult to distinguish from leukopla-kia. In some patients, the lesions are erythematous orfrankly ulcerated. Oral lesions of lichen planus may alsoinclude bullae, but this is rare. These different forms canmerge or coexist in the same patient.1 The gingivae arecommonly the site of erythematouserosive OLP.Involvement of the gingivae is described clinically asdesquamative gingivitis, but is not unique to OLP andmay feature in the presentation of other oral dermato-ses, especially pemphigoid and pemphigus.

Special investigations

Biopsy and histopathological investigations

The clinical features alone may be sufficiently diagnos-tic, particularly when presenting with the classicreticular form. The evidence regarding the need andvalue of biopsy for histological confirmation of thediagnosis is not definitive. Studies have shown variabilityin both inter-observer and intra-observer reliability inthe clinicopathological assessment of OLP.6 As OLP is achronic disorder that often requires long-term treatment

and monitoring, biopsy would be prudent clinicalpractice, particularly when the disease does not presentwith its typical manifestations, or when there is concernand therefore need, to exclude dysplasia or malignancy.1

Furthermore, in severe disease warranting treatmentwith high-dose systemic corticosteroid therapy or potentsteroid-sparing immune-suppressant agents, then aconfirmatory biopsy would be highly appropriate.

Laboratory investigations

These are indicated in patients with severe OLPwarranting high-dose systemic corticosteroids, withthe need to exclude underlying infectious diseases thatcan be reactivated by the corticosteroids (e.g., HIV,Hepatitis B and C, and tuberculosis). Similarly, ifconsidering treatment with a suitable steroid-sparingsystemic agent (e.g., hydroxychloroquine, azathioprineor methotrexate), then routine full blood count, andtesting of liver and renal function may be worthwhilefor baseline assessment and monitoring in patientsneeding long-term management.

Differential diagnoses

There is a spectrum of oral lesions that resembles OLPboth clinically and histopathologically.7 These lichenplanus-like (lichenoid) lesions include the followingconditions: (1) oral lichenoid contact lesions (OLCL) asa result of allergic contact stomatitis (delayed immunemediated hypersensitivity). They are seen in directtopographic relationship to dental restorative materials,such as amalgam. In regards to the approach to oral

Fig 1. Characteristic white interlacing striae seen with oral lichenplanus present on the buccal mucosa.

24 2010 Australian Dental Association

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lichenoid contact lesions, the value of patch testingremains controversial;711 (2) oral lichenoid drugreactions (OLDR), wherein oral andor cutaneouslesions arise in temporal association with the takingof certain medications, e.g., oral hypoglycaemic agents,angiotensin-converting enzyme inhibitors, and non-

steroidal anti-inflammatory agents. Confirmation ofthe diagnosis of an oral lichenoid drug reaction may bedifficult, since empiric withdrawal of the suspected drugandor its substitution by an alternative agent may becomplicated;12,13 (3) oral lichenoid lesions (OLL-GVHD) of graft-versus-host disease are confined toallogeneic haematopoietic stem cell transplant recipientswho have developed acute, or more commonly, chronicgraft-versus-host disease (cGVHD). There is evidencethat there is a greater risk of malignant transforma-tion with OLL-GVHD than seen with OLP.14

The oral presentation of discoid lupus erythematosus

(DLE) can also present with reticular or plaque-likelesions, but it is an uncommon condition that tends topresent very much unilaterally, so indicating biopsy forhistopathological and direct immune-fluorescenceinvestigations, the latter being most useful in distin-guishing OLP from DLE.15

Additional measures

Referral for examination by a dermatologist or gynae-cologist should be considered, depending on thepresenting signs and symptoms reported by the patient.

Treatment

An essential first step is patient education as to thechronic nature of OLP and that therapy is not curative,but directed at relieving their symptoms. For treatmentto be effective, patients require education regarding theneed to be compliant with the recommended therapy.Instilling in patients the need for ongoing monitoring,not only for the patients response to treatment, but formalignant transformation is also important.

Supportive measures

The elimination of precipitating or provoking factors isan important initial step in the management of symp-tomatic OLP. The undertaking of active measures toresolve or minimize mechanical trauma from dentalprocedures, sharp cusps, rough dental restorations, andill-fitting prostheses, or chemical trauma from acidic,spicy, or strongly flavoured foods and beverages shouldbe encouraged. Of themselves, such supportive mea-sures can lead to symptomatic improvement, or, morerarely, resolution of the disease.

The accumulation of bacterial plaque, often as aresult of the discomfort associated with oral hygiene

procedures in patients with gingival involvement, mayalso exacerbate the condition. The use of supplementaloral hygiene measures, including the use of alcohol-freechlorhexidine gluconate mouthrinses, may be helpful insuch cases.16

Patch testing and removal of lichenoid-inducingdental restorative materials

Idiopathic OLP needs to be distinguished from OLCL,most commonly seen in direct topographic relationshipwith amalgam. Cutaneous patch testing, undertaken bya clinician skilled and experienced in reading thecutaneous response to a variety of test agents can beuseful to confirm the diagnosis of an OLCL,7,8 espe-cially in severe, symptomatic cases, in which wide-spread replacement of the amalgam fillings is beingconsidered, given the expense in time and money to the

patient concerned. The benefit of such patch testing isto ensure that the alternate dental restorative materialsalso, in turn, do not incite a lichenoid contact reaction(e.g., as has been seen with gold and even compositematerials). In select cases, and if practical, consider-ation should be given to the replacement of thoseisolated restorations, seemingly in direct topographicrelationship with a lichenoid oral mucosal lesion,particularly if symptomatic, with an alternate material,but the patient needs to be counselled that this may notnecessarily prove beneficial. As an interim step, tempo-rary coverage of the suspected inciting material may beconsidered to determine if resolution of the OLCLoccurs before undertaking definitive removal andreplacement of the suspected inciting material.

Pharmacotherapy (Table 1)

Given the immune-mediated aetiology of OLP (andsimilar conditions such as mucous membrane pemphig-oid (MMP)), the aim of therapy is to minimize orrestrain the bodys immune-mediated inflammatoryresponse, but without risking the activation of oppor-tunistic infections. Treatment should be kept as simpleas possible and should not inordinately burden the

patient with complex, unwieldy or protracted treat-ments that result in non-compliance. Therefore, topicalcorticosteroids remain the mainstay of treatment.1,17

Unfortunately, there are only limited evidence-basedstudies regarding the therapeutic interventions in OLP,and so treatment remains largely empirical.1

Topical treatments: home remedies andover-the-counter (OTC) preparations

Patient prepared saline mouthwashes are of very limitedclinical utility, somewhat palliative, and do not addressthe aetiological factors seen in OLP, but may facilitate


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oral hygiene. Patients often self-prescribe and use avariety of OTC antimicrobial mouthwashes in themistaken understanding that OLP may be infective innature, but often complain of their astringency,

especially the alcohol-containing mouthwashes (and auseful clue as to the diagnosis).

Kenalog in Orabase is one topical corticosteroid(0.1% triamcinolone) preparation that has the distinct

Table 1. Therapeutic agents useful in treating oral dermatoses

Medication Dose ContraindicationsPre-therapeuticinvestigations Monitoring Adverse reactions

Corticosteroids(steroids)

prednisolone: n%(1) 1 mg per kgbodyweight of the

patient for 4 days(or longer inpemphigus) withrapid taper untilclinical remissionoccurs n%(2)


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advantage of being mixed with a vehicle for applyingmedication to the oral surfaces Orabase (composedof gelatin, pectin and carmellose in a Plastibase(hydrocarbon gel ointment base)).1 The use of such anadhesive addresses an important therapeutic issue intreating OLP, i.e., having sufficient contact time

between the medicament and the mucosal lesion(s) ofOLP. It maintains the medication in close contact withthe lesion and provides a protective covering thataugments the effects of the corticosteroid.

Prescription treatments: topical corticosteroidpreparations

Topical corticosteroids come in a range of strengths,rated from mild (hydrocortisone) to moderate (beta-methasone valerate) to highly potent (clobetasone) andmeans of delivery by pastes, ointments, gels or as

inhaled agents (as used in asthma treatment). Allagents, used in a variety of delivery methods havedemonstrated some efficacy in treating OLP.1 How-ever, the basic principles guiding topical corticoster-oids therapy is firstly to use the lowest strength agentpossible to achieve a therapeutic benefit, and secondly,for oral mucosal lesions (as opposed to skin condi-tions), to favour the use of adhesive-containingpreparations to prolong contact time, and so avoidthe agent being simply washed away by the ever-present saliva.

Compounded preparationsEmpirically, patients report modest to good responsesto the use of moderate, to highly potent topicalcorticosteroids such as betamethasone valerate mixedwith an equal amount (by weight) of Orabase, used twoto four times daily (after meals) given they are suitablyadhesive. One limitation is that they often need to beprepared by specialist compounding pharmacists. Asecond limitation is many patients find this mixtureunpleasant and tacky. Use of specially fabricatedmodified topical fluoride trays, with extended coverageof the gingiva and adjacent alveolar mucosa to hold

topical agents in place in the treatment of the desqua-mative gingivitis form of OLP are reported to behelpful, but again, patient compliance can be poor.1

Potent corticosteroids, such as dexamethasone, com-pounded as a mouthwash suspension (0.1% strength 40 mg Dexamethasone mixed with 400 ml sterilewater) are better tolerated by patients.18 However,patients must be carefully instructed in their use,emphasizing that it is to be used as a rinse, for at leastthree minutes (for sufficient therapeutic contact time),at most four times a day (after meals) and to spit outwell, to minimize systemic uptake of this highly potentcorticosteroid and thereby avoid its adverse effects.

Antifungal agents

Supplemental use of antifungal agents, such as *Dakt-arin (miconazole) Oral Gel, or chlorhexidine-con-taining mouthwashes is warranted given the risk ofcandidial overgrowth and possible infection secondary

to the use of the corticosteroids (whether they be usedtopically or systemically).

Systemic agents: corticosteroids

Systemic corticosteroids are used in two ways: firstly, asa short-term pulse dose of prednisolone up to 0.5 mgper kilogram (of the patients) body weight for a shortperiod of time (four days or less and then rapidlytapered) to bring about control of severe ulcerative OLPor in patients with multiple, highly active, sites of lichenplanus. Secondly, longer-term, to supplement topical

therapies, at sub-physiological doses (equal or less than7.5 mg prednisone (or equivalent) daily.1 Monitoringfor the principle side effects (and other adverse effects)of systemic corticosteroid therapy, hypertension, dia-betes mellitus, gastric ulceration and osteoporosis isessential and should be undertaken by clinicians skilledin the use of such agents and familiar with their sideeffects.

Corticosteroid alternatives

Retinoids (topical and systemic)Overall, the published studies suggest that retinoids arepotentially effective in the treatment of OLP, butprobably inferior to corticosteroids.19 Systemic reti-noids are associated with a number of serious adverseeffects that would prohibit their routine use for themanagement of OLP, and include elevatedderangedtransaminase levels, hyperlipidaemia, cheilitis, drynessand desquamation of the skin, alopecia, and dystrophicnail formation, as well as being teratogenic andtherefore their use in women of child-bearing age iscontraindicated.

Topical calcineurin inhibitors

Cyclosporine is one of the oldest of such agents, but itis relatively expensive and unpleasant tasting, withstudies showing an improvement in the oral symptomsthat is not significantly better than 1% triamcinolonepaste.20

Tacrolimus and pimecrolimusTacrolimus and pimecrolimus are newer calcineurininhibitors,21 with an improved safety profile in com-parison with cyclosporine but there are only limited

*Azoles (topical or systemic) are contraindicated in patients taking

Warfarin.




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studies as to their benefits. They are expensive and theUnited States Food and Drug Administration (FDA) hasa black box warning attached to the use of theseagents because of a theoretical increased risk ofmalignancy (squamous cell carcinoma and lymphoma)in patients using topical tacrolimuspimecrolimus for

cutaneous psoriasis. Therefore, the use of these agentsshould be restricted and patients should be made awareof these concerns.22

PhototherapyThere is a single study of the benefits of phototherapyusing psoralen ultraviolet A light (PUVA) and whichwas included in a recent Cochrane review. However,UV light has a known oncogenic potential and there-fore, its use for OLP is questionable.23

Other andor steroid-sparing systemic medications

These agents are indicated in patients with refractoryLP, confined to the oral cavity, or also involving extra-oral sites, requiring systemic corticosteroids for control.There is limited evidence supportive of a few potentiallyuseful agents and the use of such agents is best restrictedto clinicians highly familiar with these drugs and,importantly, their adverse effects: (1) lysosomotropicamines (the antimalarials chloroquine and hydroxy-chloroquine): hydroxychloroquine, at doses of 200 to400 mg daily, have been effective for OLP;24 (2)azathioprine is a successful steroid-sparing agentfor cutaneous lichen planus, but there is limitedpublished evidence suggesting it may have a similarrole in recalcitrant OLP at doses ranging from 12 mgper kilogram (patients bodyweight) daily; (3) othersystemic agents: a variety of other immune-suppressantor immune-modifying agents have been trialled in OLP,including Dapsone (diamino-diphenyl sulfone anantituberculoticantileprotic medication), systemic cal-cineurin-inhibitors, such as cyclosporine and morerecently the chemotherapeutic agent and the folinicacid inhibitor, methotrexate. Evidence for the use ofsuch agents is poor, limited to case series or casereviews, and these agents all have significant, poten-

tially highly adverse side effects that would demandgreat caution in their use for OLP.

PROGNOSIS AND OUTCOME

Protracted involvement is typical for OLP, averaging oneight years, and ranging up to 20 or more years. Inmany cases, OLP inexplicably burns out allowing forthe cessation of any therapeutic interventions. How-ever, some patients may suffer from the cycle of chronicinflammation followed by healing with scarring, withresultant microstomia, if the bucco-labial mucosa isinvolved, or loss of buccal sulcal depth, making the

provision of oral hygiene by the use of a toothbrushdifficult for the patient. In such cases, elective removalof the more posteriorly placed teeth, especially unop-posed, non-functional molar teeth may merit consider-ation. Plastic surgery interventions to relieve themicrostomia are sometimes indicated but are painful

and can be of limited benefit.

Malignant transformation

The potential for OLP to undergo malignant transfor-mation is controversial. If there is a risk, the risk is verydifficult to quantify and possibly so low that it is verydifficult to determine if OLP is truly associated with asignificant risk for malignant transformation. Prudencedictates treating OLP as a potentially malignant lesion.1

If this approach is favoured, then ongoing, and at theleast, annual monitoring, of the oral mucosa by a

clinician experienced in the management of OLP isindicated. Any lesion suspected to harbour dysplasiaandor frank malignancy (oral squamous cell carci-noma) merits biopsy, and histopathological assessment,preferably by a pathologist experienced in oral patho-logy. Clinical suspicion should be aroused in the caseof a lesion (or lesions) not typical for OLP, a lesion thatis heterogeneous in texture and colour (a mixture oferythema and keratosis), or any isolated area of mucosathat remains unresponsive to therapeutic interventions,such as persistent ulceration despite clinical improve-ment in the remainder of the mucosa affected by theOLP. Before undertaking a biopsy, considerationshould be given to a trial of topical (and if indicatedsystemic) corticosteroids and anti-fungal treatments tolessen any associated inflammatory or infectiouschanges that, on histopathological assessment, maymask the degree of dysplasia or malignancy within thelesion.

Dentists have a crucial role in the diagnosis of OLP, acommon immune-mediated disorder and its manage-ment, especially initiating supporting measures, of whatcan be a chronic and very troubling condition for thepatient. Management entails patient education as to itsimmune-mediated inflammatory nature, the chronicity

of the condition and the value and limitations of anytherapeutic intervention. The mainstay of treatment istopical corticosteroid therapy that relies on patientcompliance, that is regular and, when required, usedfrequently, to be effective. Systemic corticosteroidtreatment has a role, as does select systemic alternateor steroid-sparing agents but these are best used byspecialist clinicians familiar with their proper use andthe adverse side effects of such agents. All cliniciansinvolved in the delivery of dentaloral health care to apatient with OLP need to provide monitoring of theoral mucosa for any changes that may herald malignanttransformation.


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ERYTHEMA MULTIFORME

Erythema multiforme (EM) is part of a spectrum ofcomplex, immune-mediated, reactive, muco-cutaneousdisorders that often presents with oral, especially, labialmucosal erythema, blistering and ulceration.25,26 Thisspectrum encompasses a range of four clinical conditions(Table 2) that overlap in regards to their clinical featuresand suspected aetiology and pathogenesis: (1) EM minorwith predominantly cutaneous involvement with theappearance of the classic target lesions and infre-quently, only mild oral mucosal involvement; (2) EMmajor with cutaneous and mucosal involvement of atleast one other site, apart from the oral mucosa (Figs 2aand 2b). Both of these conditions are relatively benign,

self-limiting diseases thought to be more stronglyassociated with an infectious trigger; (3) Stevens Johnsonsyndrome (SJS) is a more severe, fulminating conditionwith involvement of up to 10% of a patients bodysurface area; and (4) toxic epidermal necrolysis (TEN) ischaracterized by epidermal denudement in excess of30% of the bodys surface area. These latter twoconditions are more likely to be triggered by a drug(50 and 95%, respectively) (Table 2).25,26

The aetiology and pathogenesis of EM remainobscure. Regardless of what serves as the trigger,the process culminates in cytotoxic CD8+ T-cellinduced apoptosis and necrosis of the basal keratino-

cyte cells, probably mediated by epithelial surfaceantigens common to, or shared with the triggeringinfectious agent or drug. Cytokines, mostly tumournecrosis factor alpha (TNF-a), are found in the lesionaltissue although in herpes simplex virus associated EM,gamma-interferon (c-IFN) predominates and mediatesthe epidermal damage.27

Histologically, early classic EM with cutaneous targetlesions have a prominent dermal inflammatory reactionwith oedema, vasodilation and a lymphohistiocyticinfiltrate around the blood vessels. With more severedisease, dramatic necrosis of the whole dermis may beseen, with subdermal blister formation with character-istic hydropic degeneration and necrosis of the individ-ual basal keratinocyte cells. Histologically, the mucosal

lesions demonstrate similar, non-specific, inflammatorychanges but with marked epithelial necrosis. The directimmuno-fluorescence findings are also non-specific butcan be useful in differentiating EM from other condi-tions such as pemphigoid and pemphigus.26

Epidemiology

There are only limited reliable data. Hospital admis-sions for EM and its associated conditions have beenreported as low as 4.2 per million patients per annum.28

Stevens Johnson syndrome is uncommon, possiblyaffecting 16 per million people per year with the

Table 2. Clinical spectrum of erythema multiforme (adapted from Ayangco L, Rogers RS25 and Al-Johani KA,Fedele S, Porter SR26)

Type Course Trigger Cutaneous involvement Mucosal involvement Duration Prognosisoutcome

EM minor acute, self-limiting,rarely recurrent

infections >10% BSA typicalsymmetrical target

lesions* and

or acrallydistributed atypicalraised target lesions

absent, or limited toone mucosal site

usually oral; orallesions: mild-severeerosionsulcers

13 weeks remits, full recovery

EM major acute, self-limitingcan be recurrent

infections >10% BSA typicalsymmetrical targetlesions* andor acrallydistributed atypicalraised target lesions

involvement of at least2 mucosal sites; oralmucosal involvementusual and the mostprominent feature ofthe disease

16 weeks generally remits

SJS acute, progressivesystemic disease

drugs >10% BSA widespreadsmall blisters, purplemacules or flat atypicaltarget lesionspredominantly foundon the torso*

involvement of at least2 mucosal sites; usuallyextensive and healswith scarring

26 weeks 10% mortality

TEN prodromal mucosal

involvementfollowed by acutedeterioration andwidespread skinlesions

drugs >30% BSA widespread

small blisters, purplemacules or flat atypicaltarget lesionspredominantly foundon the torso*

involvement of at least

2 mucosal sites; usuallysevere and extensive;heals with scarring

26 weeks 30% mortality

Abbreviations: EM = erythema multiforme; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; BSA = body surface area.Description* of skin lesions: Typical target lesions: targets: individual lesions less than 3-cm diameter with a regular round shape, well-definedborder, and at least 3 different zones, i.e., 2 concentric rings around a central disk, with one ring palpably oedematous and paler than the centraldisk. Atypical target lesions: round, oedematous, palpable lesions, similar to typical target lesions but with only 2 zones andor a poorly definedborder. Flat atypical target lesions: as for atypical target lesions, but non-oedematous, with central blister.




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reported incidence of TEN in Western Australia being0.4 cases per million head of population.28,29

Overall, the peak age of occurrence for EM andrelated disorders, apart from TEN, is in the teenageyears through to the early 20s and predominantly inyoung males. The mean peak age of onset for TEN isreported to be 63 years with a predominantly female tomale ratio of 3:2.29,30

MANAGEMENT

Diagnosis

EM and its variants are diagnosed principally by theirabrupt clinical presentation and features, with special

investigations such as biopsy for histopathology anddirect immunofluorescence useful in excluding condi-tions such as pemphigoid, pemphigus, and bullouslichen planus that may present with similar clinicalcharacteristics. In EM major, the oral mucosa is themost commonly involved mucosal site, but any mucosa

can be involved, including the epithelial lining of thetrachea, bronchi, and gastrointestinal tract, as well asthe genitalia. Erythematous macules precede vesiculo-bullous formation of the mucosa that rupture, leavingirregular superficial painful ulcers, with a markederythematous halo, or develop into broad areas ofwhite, desquamating, necrotic mucosa. The lip lesionsare characteristically, markedly haemorrhagic.25,26

SJS is a more severe disease, characterized bysignificant oral mucosal involvement, plus conjunctivalandor genital mucosal involvement, and more exten-sive skin involvement that generally follows several

days later. The muco-cutaneous lesions last up to sixweeks and reflecting the more significant diseaseprocess can heal with scarring, so resulting in laryngeal,conjunctival and vaginal strictures.25,26

TEN presents with the oral lesions typical for EMmajor, but the skin involvement is extensive, withconsequently up to 30% of the body surface denuded,and resembling second degree burns. Indeed, optimalcare for patients with TEN is in a specialized burnsunit, with attention to the critical issues of fluid loss,electrolyte disturbance and secondary infection.30

Special investigationsThere are no tests that are pathognomonic for EM andits variants. Biopsy for histopathology and directimmune-fluorescence are only useful in excluding con-ditions that can present similarly. Laboratory investi-gations are directed in determining any recent infectionthat may have triggered the EM. Human Herpes Viruses1 and 2 (HSV-1 and 2) are a very common trigger,preceding the presentation of EM major by up to14 days, reportedly in some 70% of cases. The othercommonly reported infectious trigger is Mycoplasmapneumoniae infection. For SJS and TEN, drugs, partic-

ularly anti-convulsants such as carbamazepine (Tegre-tol), phenytoin (Dilantin), phenobarbitol and sodiumvalproate are frequently implicated.26

Treatment

There are no systematic reviews detailing the besttreatment for EM major, or its more severe variants.The key aspects of care are firstly, identification and, ifpractical, treatment of the infectious trigger, or identi-fication (from the history) and withdrawal of thesuspected causative drug. Secondly, the use of im-mune-modulating therapy of which historically the

(a)

(b)

Fig 2. (a) Typical haemorrhagic crusting of the lips seen witherythema multiforme. (b) Typical cutaneous target lesions of

erythema multiforme.


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mainstay has been systemic corticosteroid therapy.However, the use of systemic corticosteroids is miredin controversy, with some authors claiming a higherrate of adverse outcomes for patients placed onsystemic corticosteroids, particularly in SJS and TEN.30

The extent of the supportive measures are scaled to

the severity and extent of the muco-cutaneous involve-ment and include in general, effective pain control,often necessitating opiates, limiting alimentation, andconsidering enteral feeding, intensive nursing, especiallyskin care, antibiotics, wound management, includingdebridement, and attention to maintenance of patientfluid and electrolyte balance.

PROGNOSIS AND OUTCOME

For EM major the muco-cutaneous lesions remit by sixweeks, usually healing with little if any scarring. For SJS

and TEN, healing only starts to occur some two, evensix weeks after onset, with a substantial risk of scarring.Mortality is reported to be as high as 70% for patientswith TEN, predominantly from infection.30 Recurrentforms of EM major, SJS and TEN have been reported.

Dental practitioners have a critical role in thediagnosis of EM major and its more severe, potentiallylife-threatening variants, SJS and TEN, as well ashaving a role in supportive care, especially pain controland ensuring proper alimentation.

MUCOUS MEMBRANE PEMPHIGOID

Pemphigoid is the general term applied to severalchronic conditions that are classified as immune-

mediated sub-epithelial blistering diseases characterizedby vesicles or bullae that break down to leave raggedulcers that affect epithelial surfaces, particularly themouth. Historically, pemphigoid was broadly subdi-vided into only two main conditions: (1) bullouspemphigoid that predominantly affects the skin, and

rarely, mucosa; and (2) benign mucous membranepemphigoid also known as cicatricial pemphigoid, butnow more simply as mucous membrane pemphigoid(MMP), that conversely, overwhelmingly affects mu-cosa and infrequently the skin.31,32

Mucous membrane pemphigoid is an antibody med-iated autoimmune disease. To understand MMP, itneeds to be appreciated that auto-antigenic antibodies,predominantly, IgG (although IgA variants are known)are directed against various antigenic sites found on thecomplex array of proteins that make up the structure ofthe hemidesmosome. The hemidesmosome is the sub-

microscopic structure, seen best under electron micros-copy that anchors the basal epithelial cells to thebasement membrane. Immunologically, MMP is char-acterized by the deposits of predominantly IgG anti-body (97%) with complement factor C3 and to a lesserextent with IgA (27%) or IgM (12%) antibodiesdirected at a variety of differing antigens (that makeup the varying subtypes of MMP) within the basementmembrane zone.32 It is now apparent that at least sixsubsets of MMP exist, on the basis of different patternsof immunopathology and antigenic specificity (targets)of the autoantibodies (Table 3).32 The result of thisantibody-complement complex is seen histologically,with separation at the junctional epithelial basementmembrane zone, giving rise to a sub-basilar split. This is

Table 3. Pemphigoid subtypes as determined by clinical features and antigen binding sites (adopted from Bagan J31)

Clinical subtypeClinical

presentationsites

Direct immuno-fluorescence (DIF)

findings

Indirect immuno-fluorescence (IIF)

findings Main target antigens

Cicatricial pemphigoid (CP) oral mucosa, othermucosal sites, skin

IgG and C3deposition at BM

frequent 230 kDa (BP1 Ag)180 kDa (BP2 Ag)b4 Integrin sub-unitLaminin5

Oral mucous membranepemphigoid (OMMP)

oral (only) IgG and C3deposition at BM

rare 230 kDa (BP1 Ag)180 kDa (BP2 Ag)

Laminin 5 and 6a6 Integrin sub-unit168 kDa

Ocular cicatricialpemphigoid (OCP)

ocular (only) IgG and C3deposition at BM

rare Laminin 5205 kDa

Anti-laminin 5 pemphigoid oral mucosa, other mucosalsites, rarely skin

IgG and C3deposition at BM

rare Laminin 5

Anti-p200 pemphigoid ? ? ? 200 kDa protein of the dermo-epidermaljunction (distinctfrom other antigensites)

Not yet specified ? ? ? antibodies against morethan one antigen

Abbreviations: BM = basement membrane; BP = bullous pemphigoid; C3 = complement component; kDa = kiloDalton.




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seen clinically as a blister underlying the full thicknessof the epithelium, and which can last hours to days ifleft undisturbed, before breaking down to leave apainful ulcer.

Occasional drug-induced MMP has been reported,associated with penicillamine (D-Penamine), a heavy-

metal chelator used in rheumatoid arthritis and the loopdiuretic agent, frusemide (Lasix, Urex).32

Epidemiology

The epidemiology of MMP is unclear. Retrospectiveimmune-fluorescent studies suggest that MMP has anannual incidence of 1.59.6 105 population (esti-mated to be up to three times more frequent thanpemphigus).32

MMP is predominantly a disease of women, with amean age at onset of 5162 years.32 Children are rarely

affected.

MANAGEMENT

Diagnosis

The clinical phenotype known as MMP is not a singleentity. It includes patients with oral lesions only, andothers with involvement of the skin andor other mucousmembranes, or occasionally other systems. The mostcommon areas of involvement are the oral cavity (85%)and conjunctivae (64%).32 The oral mucosa is often theinitial site of MMP lesions. The term oral mucousmembrane pemphigoid (OMMP) is often used whenMMP is limited to the oral cavity with no other mucosalinvolvement and ocular cicatricial pemphigoid (OCP)is used when MMP is limited to the conjunctivae.

Oral mucosal lesions

Patients present with bleeding, pain, dysphagia ordesquamation of the oral mucosa. Vesicles or bullaemay occur anywhere on the oral mucosa, and there may

be a positive Nikolsky sign, where firm slidingpressure with a finger separates normal-appearingepithelium from the underlying lamina propria, result-ing in the immediate formation of a vesicle or erosion.The blisters rupture leading to pseudo-membranecovered, irregularly shaped ulcers with a yellowish

slough and surrounded by an erythematous, inflamma-tory halo. The gingiva is the commonest site involved(Fig 3), followed by the hard and soft palate, buccalmucosa, and tongue. The oral lesions rarely scar.31,32

Ocular lesions

Ocular manifestations have been reported to occur in 3to 48% of patients with oral lesions.33 Ocular involve-ment usually begins as chronic conjunctivitis withsymptoms of burning, irritation, photophobia andexcess tearing. Vesicles are rarely seen in the conjunc-

tiva and ulceration is seen only in advanced aggressivedisease. Scarring following repeated fibrosis can lead tosymblepharon (partial or complete adhesion of thepalpebral conjunctiva of the eyelid to the bulbarconjunctiva of the eyeball), ankyloblepharon (fusionof the sclera and palpebral conjunctivae), and greatdiscomfort from entropion (the eyelids fold inward torub the corneal surface) and trichiasis (malpositionedeyelashes touching the cornea or conjunctiva). Thecombination of entropion and trichiasis may lead toblindness.32

Other sitesCutaneous involvement is uncommon (up to 25% ofpatients) and is limited to the face, neck, scalp, axilla,trunk and extremities. Some patients may developlesions affecting the larynx, oesophagus, nasal andgenital mucosa.3234

Clinically, there are a number of differential diagno-ses to consider and include pemphigus, oral lichenplanus, erythema multiforme (and its variants), anginabullosa haemorrhagica, dermatitis herpetiformis orlinear IgA disease, andor epidermolysis bullosa acqui-sita (EBA).31,32,34


Biopsy (histopathological and DIF investigations)

Definitive diagnosis is based on biopsy of perilesionaltissue with histological and direct immuno-fluores-cence (DIF) examination.31,32,34 Histologically, MMPis characterized by junctional separation at the levelof the basement membrane giving rise to a sub-basilarsplit as in other forms of pemphigoid. The findingsfrom the DIF microscopy are the most useful. TheDIF shows deposits of IgG and C3 in a homogeneous

Fig 3. Desquamative gingivitis, a clinical presentation (not acondition) seen with oral lichen planus, and on occasion, mucous

membrane pemphigoid.


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linear manner in the basement membrane zone(BMZ) along the epithelial-connective tissue junc-tion.31,32


As for OLP, these are generally not required, exceptfor patients with severe MMP, warranting high-dosesystemic corticosteroids with the need to excludeunderlying infectious diseases that can be reactivated.A similar approach is required and if consideringsuitable steroid-sparing systemic agents such asazathioprine or, for MMP in particular, cyclophosph-amide, is warranted for long-term management.

Indirect immunofluorescence

Indirect immunofluoresence findings using the sub-

basement membrane antigen titre can be inconsistent,and so usually, unhelpful. However, IIF done on salt-split epithelial substrates (ss-IIF) can be useful indistinguishing MMP from EBA. Salt-split substratesuse epithelium, in which the lamina lucida of thebasement membrane has been split at the middle, leavingexposed the target antigens for MMP andor EBA. InMMP the circulating antibodies bind to the roof, base, orboth, of the salt-split epithelial substrate, consistent withthe heterogeneous nature of the target antigens seen inMMP. In contrast, in EBA the circulating antibodies onlybind to the base and so ss-IIF can be useful indifferentiating MMP from EBA.31,32

Treatment

The treatment for MMP, especially oral MMP isconsistent with that already outlined for the treatmentof OLP. The exception is that the tetracycline antibi-otics and derivatives, such as minocycline (at doses of50 mgday), and the nitrogen mustard analogue andalkylating agent, cyclophosphamide (at 2 mg per kilo-gram bodyweight per day), are more useful as possiblesteroid-sparing agents, for intractable disease.35,36

Prognosis

Remission can be induced with treatment althoughrelapse, especially of the ocular form, is common, sopatients will need ongoing monitoring and educationabout the need to return ifwhen they have recurrenceof their disease. MMP has no known predilection toundergo malignant change, as is the concern with OLP.

PEMPHIGUS VULGARIS

The word pemphigus is derivative from the Greekterm pemphix meaning bubble or blister. Pemphigus

is a group of autoimmune diseases (Table 4) character-ized by intra-epithelial blistering, resulting in superficialvesicles or bullae that easily rupture, resulting inulceration of mucosal andor cutaneous sites. Pemphi-gus vulgaris (PV) is the most common and clinically themost aggressive variant, being associated with signifi-

cant morbidity and mortality, composing 70% of allreported cases.37 Pemphigus vulgaris commonly andinitially affects the oral mucosa and then the skin.Other mucosal sites may also be involved, including themucosa of the conjunctivae, nose, oesophagus, pharynxand larynx, and genitalia.37

Epidemiology

Pemphigus vulgaris affects 0.10.5 patients per 105

population per year.37 It is more prevalent in certainethnic groups, in particular Ashkenazi Jews and people

of Mediterranean and South Asian background. This isreflected in the association with certain HLA subtypes:HLA-DR4 (DRB1*0402) especially seen in Ashkenazi

Jews, and DRx14 (DRB1*1041) and DQB1*0503 inpatients of European and Asian backgrounds, respec-tively.38

The male to female ratio is approximately equal. Themean age of onset is between 50 to 60 years of age,although the condition has been described in childrenand elderly patients.37

Pemphigus vulgaris is an autoantibody-mediatedcondition, similar to pemphigoid, but the antibody-complement complexes are directed at the inter-epithelial attachment of the epithelial cells and notthe attachment of the basal epithelial cells to thebasement membrane that characterizes MMP. Specificto PV, the IgG serum autoantibodies are directedagainst a cadherin-type cell adhesion molecule in thestratified squamous epithelium that binds keratino-cytes to one another. The main adhesion moleculeantigen target seen in PV is desmoglein 3 (Dsg3).However, 50% of patients also have autoantibodies toDsg1.39 Oral epithelium expresses high concentrationsof Dsg3 whereas skin expresses both Dsg3 and Dsg1.As a result, oral lesions develop at an early stage.

However, once Dsg1 antibodies are evident, thedisease progresses to involve skin and other mucosalsites.39 The proportion of Dsg1 and Dsg3 antibodiesappears to be related to the clinical severity of PV;those with only Dsg3 antibodies have oral lesionspredominantly.39

This antigen-antibody interaction activates the com-plement cascade by the release of inflammatory medi-ators and recruitment of activated T cells. Damage tothe intercellular area between keratinocytes leads toapoptosis, resulting in loss of cell-to-cell adhesion(acantholysis) and subsequent intra-epithelial blister-ing.37




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Table 4. Clinical and immunohistochemical variants of pemphigus

Disease and subtype(s)(alternate terms)

Clinical presentationNatural history

prognosisoutcome Target antigensOral Cutaneous

Pemphigus vulgaris(PV)

Common.Usually the first

site involved

Commonest and most aggressive form of pemphigus:oral mucosal involvement common and often first site

of presentation leading to extensive skin involvement.

Fatal if untreatedGood with

treatment

Desmoglein 3(Dsg 3 is more

common in oralepithelium)

(& Desmoglein 1(Dsg-1 & 3 areboth found inskin))

Pemphigus vegetans Rare (in all 3forms ofpemphigusvegetans)

Uncommon and less aggressive clinical variant of PV:presents with large verrucous confluent plaques andpustules localized to flexural areas (axillagroin).

Often progressesto pemphigusvulgaris

Pemphigus vegetansof Neumann

Often begins and ends as typical PV. Needs moreintense immune-suppression than seen with PV, withpatients troubled by chronic relapses (and remissions).

Frequent relapses(even withtreatment)

Pemphigus vegetansof Hallopeau

Relatively benign, usually very well localized disease. Prolongedremission (withtreatment)

Pemphigus foliaceus(PF)

Rare All forms of PF are characterized clinically by superficialcutaneous blisters and erosions seen on histology assubcorneal acantholysis.

More benigncourse than PV,with prolongedremission.

Desmoglein 1

Pemphiguserythematosus

(Senear-Ushersyndrome)

Very rare condition with the combined features ofpemphigus foliaceus and SLE.

Endemic pemphigus(Brazillianpemphigus orFogo Selvagem(FS))

PF and FS are identical clinically, histologically, andserologically but differ significantly, epidemiologically,with marked geographic clustering in Brazil, being adiseases of people resident inor near the rainforests.

The autoimmune response in FS is thought to betriggered by a putative environmental factor.

IgA pemphigus Rare (all 3 formsof IgApemphigus)

Rare, characterized by pruritic, flaccid vesicles andorpustules in annular pattern with central crusting,sometimes hypopyon* of the eye. Pathogenesis: relatedto the neutrophilic infiltrate in the epidermis ratherthan solely to the binding of IgA to target epidermalantigens. DIF: IgA (cf IgG seen in all other forms ofpemphigus) deposits in lower epithelium or entireepidermal cell surfaces.

Recalcitrant totreatment withcorticosteroids

Desmoglein 3 (&Desmoglein 1)

Subcorneal pustulardermatosis(Sneddon-Wilkinsondisease)

Subcorneal (beneath the stratum corneum) blistercontaining neutrophils with epidermal acanthosis andspongiosis, results in superficial fragile blistering.

IntraepidermalneutrophilicIgA dermatosis

Deeper, intra-epidermal blister containing neutrophilswith epidermal acanthosis and spongiosis, results inmore marked blistering and consequent ulceration.

Paraneoplasticpemphigus

Common & verysevere

Polymorphous skin eruption, consisting of blisters,erosions, and targetoid lesions; severe mucousmembrane involvement.

DIF: IgG deposits on entire epidermal cell surfaces +)granular-linear complement auto-antibodies to ratbladder epithelium in 75% of cases.

Fatal Desmoglein 3,Desmoplakin 1,Desmoplakin 2,BP 230,evoplakin,periplakin,others

Familial benignchronic pemphigus(Hailey-Haileydisease)

Rare Not a true form of pemphigus, as it is not antibodymediated. AD pattern of inheritance

It presents a chronic recurrent bullous and vesiculardermatitis of intertriginous areas that is characterizedhistologically by suprabasilar acantholysis.

Pathogenesis: heterozygous mutations of the ATP2C1gene leads to a malfunction of the encoded proteinhPMR1 - hPMR1 being a high-affinity calciumtransport ATPase pump of the Golgi complex. A lowlevel of intracellular Ca2+ induces prematurekeratinocyte proliferation, which leads todysfunctional desmosomal proteins and thus abnormalkeratinocyte adhesion.

chronic,relapsingremitting course

Desmocollin 1

Abbreviations: PV = pemphigus vulgaris; PF = pemphigus foliaceous; SLE = systemic lupus erythematosus; FS = Fogo Selvagem; DIF = directimmuno-fluorescence; cf = in contrast; BP = bullous pemphigoid; AD = autosomal dominant; Ca 2+ = calcium ion.*hypopyon = sterile leukocytic exudate; seen in the anterior chamber of the eye.


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Some drugs have been reported to induce PV,including the anti-mycobacterial antibiotic, rifampicin.More recently, associations have been reported withpenicillamine as well as the anti-hypertensive ACE(angiotensin-converting enzyme) inhibitor, captopril,and other thiol-containing compounds.37

Paraneoplastic pemphigus is the rarest, but mostserious form of pemphigus, that presents with featurestypical for PV. Paraneoplastic pemphigus is again animmune-mediated disorder, initiated by an underlyinglympho-reticular or haematological malignancy. It ishypothesized that antibodies principally evoked anddirected against the malignant cells, inadvertentlytarget antigens that share characteristics with thetumour cells, but are found instead in the mucosa andskin. Paraneoplastic pemphigus has a poor prognosiswith a mortality rate, regardless of treatment,approaching 90%.40

MANAGEMENT

Diagnosis

Pemphigus vulgaris presents with oral lesions in 5070% of cases. Oral mucosal lesions may be the first andonly sign of disease, and often precede cutaneousinvolvement by an average of five months.

Oral mucosal lesions may present initially as intactvesicles or bullae that readily rupture, forming painfulill-defined, irregularly shaped erosions and ulcers(Fig 4)41 that may affect any part of the oral mucosa,although gingival, buccal or palatal lesions are mostcommon. These lesions are painful and slow to heal,but do not scar. Advanced manifestations usuallycomprise severe desquamative or erosive gingivitis,

where bullae have ruptured to leave areas of peelingtissue with red erosions and ulcers.

All oral mucosal sites may be involved, and lesionsmay spread to involve the oropharynx and larynx.Other mucosal surfaces, including the conjunctiva,oesophagus, and genitalia may also become involved.

Many patients develop cutaneous lesions, oftenpresenting as a flaccid blister containing clear fluid,which arises on normal-appearing skin. Due to theirfragile nature, being intra-epithelial (in contrast to thesub-epithelial nature of the blisters seen in pemphigoid),intact blisters are uncommon in PV, rupturing quicklyto produce painful erosions.

Patients can be Nikolsky sign positive on examina-tion of the mucosa and the skin.


Clinical suspicion that a patient has one of the vesiculo-bullous diseases warrants biopsy of perilesional tissue,with histological and DIF examination being essentialin establishing the diagnosis.

Biopsy, histopathological and direct immuno-fluorescence investigations

Histopathology demonstrates intra-epithelial vesicleformation. The earliest changes consist of intercellularoedema with loss of intercellular attachments in thebasal layer. Suprabasal keratinocytes separate from thebasal cells to form clefts and blisters. Basal cells areseparated from one another and stand like a row oftombstones on the floor of the blister, but they remainattached to the basement membrane. Acantholytic(Tzanck) cells may be seen within the vesicle.37

Direct immuno-fluorescence performed on freshtissue demonstrates IgG deposited on the surface ofthe keratinocytes forming a basket weave appear-ance. IgM and complement components such as C3may also be present.


These are required in the patient in whom PV issuspected. Indirect immuno-fluorescence is essential indetecting the circulating IgG autoantibodies that bindto epithelium. These are present in 8090% of patientswith PV. Antibody titres may also help guide prognos-tication and therapy. The preferred substrate for IIF ismonkey oesophagus or salt-split normal human skinsubstrate.42 In paraneoplastic pemphigus, the circulat-ing antibodies not only bind to squamous epithelial cellsurfaces (skin and oesophagus substrates) but alsoattach to transitional epithelium, such as rat bladder,and this is useful in differentiating PV from paraneo-plastic pemphigus.40

Fig 4. Pemphigus vulgaris typical oral presentation with shallowulceration of the soft palate.




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In addition, as high-dose systemic corticosteroidsserve as the mainstay of initial therapy for PV, there isthe need to exclude underlying infectious diseases thatcan be reactivated by the corticosteroids (HIV, Hepa-titis B and C, and tuberculosis). In addition, screeningfor the diseases initiated or exacerbated by high-dose

steroids, such as hypertension, diabetes mellitus andosteoporosis is also required.

For long-term management, almost inevitably, pa-tients with PV will need to be changed to a suitablesteroid-sparing systemic agent, namely azathioprine,mycophenolate andor rituximab (Mabthera).43

PROGNOSISOUTCOME

The severity and natural history of PV is variable, butbefore the advent of corticosteroids, most patients died.Treatment with systemic steroids has reduced the

mortality rate to 515%.37

Most deaths occur during the first few years ofdisease, and if the patient survives five years, theprognosis is good. Early disease is probably easier tocontrol than widespread disease, and mortality may behigher if therapy is delayed. Morbidity and mortalityare related to the extent of disease, the maximum doseof systemic corticosteroids required to induce remis-sion, and the presence of other diseases. Prognosis isless favourable in patients with extensive disease and inolder patients. Complications secondary to the use ofhigh-dose corticosteroids contribute to the mortalityrate, therefore steroid-sparing agents should be intro-duced as quickly as practical once clinical remission isachieved. Both azathioprine and mycophenolate, purineinhibiting cytostatic agents, with particular activityagainst T and B lymphocytes have been shown to besuccessful as steroid-sparing agents for PV. Both have adelayed onset of action, of up to 34 months, so thatslow tapering of the corticosteroids is required, corre-lated to the clinical signs of disease, in conjunction withthe introduction of these steroid-sparing agents.

Rituximab (Mabthera) is a genetically engineeredchimeric murinehuman monoclonal antibody thatbinds specifically to the antigen, CD20, a transmem-

brane molecule located on pre-B and mature B lym-phocytes. This results in B-cell lysis by complementdependent cytotoxicity (CDC) and antibody dependentcellular cytotoxicity (ADCC), as well as possiblyinducing apoptosis, causing the elimination of allcirculating B-lymphocytes. As a result, they cannottransform into active, antibody-producing plasma cells.The net result is no autoantibody is produced that cantarget the intra-epithelial, desmoglein proteins, soinducing a remission of the PV.43

The incidence and duration of true remissions inpemphigus is uncertain. The question remains iftreatment simply suppresses the manifestations of the

disease and therefore must be continuously adminis-tered, or induces complete remissions, so allowingtherapy to be discontinued. However, a recent long-term longitudinal study has been undertaken ofcomplete and long-lasting remissions (defined aslesion-free with no systemic therapy for at least six

months) in 40 patients with PV treated conventionallyand followed up for an average of 7.7 years. Fivepatients (5%) died of the disease but complete andlong-lasting remissions were induced in 25, 50 and75% of patients at 2, 5 and 10 years, respectively,after diagnosis.44 Most of the remaining patients werein partial remission or had mild disease controlled withonly a small dose of corticosteroids. It is thereforepossible to eventually induce complete and durableremissions in most patients, permitting systemic ther-apy to be safely discontinued without a flare in diseaseactivity in approximately 75% of patients after

10 years.44

It is notable that early diagnosis and the introductionof treatment, so that the PV remains confined to theoral mucosa, appears to have a critical effect onprognosis and outcome. This again emphasizes theimportant role dentists have in screening and recogniz-ing various oral mucosal diseases, such as PV.

EPIDERMOLYSIS BULLOSA ACQUISITA

Epidermolysis bullosa acquista (EBA) is a very rarenon-inheritable, mechano-bullous condition character-ized by the development of autoantibodies that targetthe Type VII collagen found in the basement mem-brane.45 In contrast, epidermolysis bullosa (EB) is aninherited form of the disease. Both diseases arecharacterized by the problem that even the slightestmechanical irritation, or trauma of the skin andor themucosal surfaces of the oral cavity and upper aero-digestive tract, results in the formation of blisters thatonly heal with scarring and severe atrophy of theaffected tissues. In EB the defect is a genetically-induced molecular derangement of the keratin fila-ments, hemidesmosomes and anchoring filaments andfibrils that attach the epidermis to the deeper dermis.

Clinically, EBA manifests very similarly to the inher-ited, but more severe and devastating, EB, but has lateronset, usually in early adulthood, and so can beconfused clinically with other blistering conditions,especially pemphigoid and its variants. The diagnosisrests on the history, biopsy with DIF to excludepemphigoid and other blistering diseases, and IIFundertaken on salt-split epithelial substrates (thatshow typical antigen binding to the base of theepithelial cells).45 Treatment is usually successful withhigh-dose corticosteroids often required in combina-tion with other immunosuppressant agents andordapsone.45 The oral complications, especially those


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resulting in microstomia can be most severe andwarrant the minimization of any dental treatment, orthe use, immediately prior to any dental treatment, ofa bolus of high-dose corticosteroids.

SUMMARYDentists need to be very familiar with the range andnumber of immune-mediated conditions that canpresent with initial or even isolated oral manifestationsgiven their potential for morbidity, the poor quality oflife of affected patients, and their potential mortality.

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Address for correspondence:Clinical Associate Professor Mark Schifter

Department of Oral Medicine, Oral Pathology andSpecial Needs Dentistry

Westmead Centre for Oral HealthWestmead Hospital

PO Box 533Wentworthville NSW 2145

Email: [email protected]

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