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Home , Aphthous stomatitis, Oral medicine, Pemphigus

OralMedicine-UpdatefortheDentalTeam

This series provides an overview of current thinking in the more relevant areas of Oral , for primary care practitioners. The series gives the detail necessary to assist the primary dental clinical team caring for patients with oral complaints that may be seen in general dental practice. Space precludes inclusion of illustrations of uncommon or rare disorders. Approaching the subject mainly by the symptomatic approach, as it largely relates to the presenting complaint, was considered to be a more helpful approach for GDPs rather than taking a diagnostic category approach. The clinical aspects of the relevant disorders are discussed, including a brief overview of the aetiology, detail on the clinical features and how the diagnosis is made, along with guidance on management David H Felix Jane Luker Crispian Scully and when to refer, in addition to relevant websites which offer further detail. : 2. : Serious Ulcers

Specialist referral may be indicated if the Practitioner feels:  The diagnosis is unclear;  A serious diagnosis is possible;  may be present;  Unclear as to investigations indicated;  Complex investigations unavailable in primary care are indicated;  Unclear as to treatment indicated;  Treatment is complex; Figure 1. Squamous cell . Figure 2. .  Treatment requires agents not readily available;  Unclear as to the prognosis;  The patient wishes this. gut and miscellaneous uncommon disorders Aetiopathogenesis may cause oral lesions which, because of the Behçet’s syndrome is a Malignant ulcers moisture, trauma and in the , which has not been proved to be infectious, A range of neoplasms may tend to break down to leave ulcers or erosions. contagious, or sexually transmitted. There are present with ulcers: most commonly these is often required to establish the many immunological findings in BS similar are (Figure 1) but Kaposi sarcoma, diagnosis. to those seen in RAS, with T suppressor cell and other neoplasms may be dysfunction, and increased polymorphonuclear seen and are discussed in Article 3. Biopsy is Mucocutaneous disorders leucocyte motility. There is a genetic required to establish a definitive diagnosis. Mucocutaneous disease that predisposition. Many of the features of BS may cause oral erosions or ulceration (or ( nodosum, arthralgia, ) are Systemic disease occasionally ) include particularly common to established immune complex A wide range of systemic diseases, Behçet’s syndrome, and a number of diseases. especially, mucocutaneous diseases, blood, diseases including lichen planus (Figure 2), occasionally or Clinical features David H Felix, BDS, MB ChB, FDS , and rarely . Behçet’s syndrome is a chronic, RCS(Eng), FDS RCPS(Glasg), FDS RCS(Ed), sometimes life-threatening disorder FRCP(Edin), Postgraduate Dental Dean, Behçet’s syndrome characterized mainly by: NHS Education for Scotland, Jane Luker, Behçet’s syndrome (BS) is a rare  Recurrent aphthous (RAS): in 90%– BDS, PhD, FDS RCS, DDR RCR, Consultant condition. It is the association of recurrent 100% of cases; and Senior Lecturer, University Hospitals (RAS) with genital  Recurrent painful genital ulcers that tend to Bristol NHS Foundation Trust, Bristol, ulceration, and serious eye disease (especially heal with scars; Professor Crispian Scully, CBE, MD, PhD, iridocyclitis) but other systemic manifestations  Ocular lesions. Iridocyclitis, uveitis, retinal MDS, MRCS, BSc, FDS RCS, FDS RCPS, may also be seen. The disease is found vascular changes, and optic may occur; FFD RCSI, FDS RCSE, FRCPath, FMedSci, worldwide, but most commonly in people  CNS lesions; FHEA, FUCL, DSc, DChD, DMed(HC), Dr from the Eastern Mediterranean countries  Skin lesions: , HC, Emeritus Professor, University College (particularly Greeks, Turks, Arabs and Jews) and papulopustular lesions and acneiform London, Hon Consultant UCLH and HCA, along the Silk route taken by Marco Polo across nodules; London, UK. eastern Asia, China, Korea and Japan.  The joints, epididymis, heart, intestinal tract,

594 DentalUpdate October 2012 OralMedicine-UpdatefortheDentalTeam

sterile subcutaneous puncture of the forearm. may precede lesions on other stratified Investigations squamous epithelia (eyes, genitals, or skin), There is no specific diagnostic or may arise in isolation. Oral EM typically test but typing for specific human leukocyte presents with macules which evolve to (HLA B5101) can help. Disease activity blisters and ulcers (Figure 3). The become may be assessed by serum levels of various swollen, cracked, bleeding and crusted. Skin proteins raised in active BS, such as the acute lesions start on the hands and/or feet but phase proteins (erythrocyte sedimentation rate subsequently spread along the limbs to involve (ESR), C-reactive protein (CRP )) or to the trunk. The lesions are initially sharply intermediate filaments. demarcated macules which evolve into target- Figure 3. Erythema multiforme presenting with like lesions (Figure 4). multiple recurrent ulcers. Minor EM affects only one site Management and may affect mouth alone, or skin, or other In the face of the difficult diagnosis mucosae. are various but typically ‘iris’ and serious potential complications, patients or ‘target’ lesions or bullae on extremities. with suspected BS should be referred early for Major EM (Stevens-Johnson specialist advice. syndrome – SJS) almost invariably involves the and causes widespread Websites and patient information lesions affecting mouth, eyes, , larynx, http://www.arthritisresearchuk.org/ oesophagus, skin and genitals. arthritis_information/arthritis_types__ symptoms/behcets_syndrome.aspx Diagnosis http://www.behcets.org.uk There are no specific diagnostic Figure 4. Erythema multiforme – skin. tests for EM. Therefore, the diagnosis is mainly Lichen planus clinical, and it can be difficult to differentiate Lichen planus is discussed in it from viral stomatitis, pemphigus, toxic Article 6. epidermal necrolysis, and sub-epithelial immune blistering disorders. Serology for vascular system and most other systems may HSV or Mycoplasma pneumoniae, or other Erythema multiforme also be involved; micro-organisms, and biopsy of perilesional Erythema multiforme (EM) is an  However, very non-specific signs and tissue, with histological and immunostaining uncommon, acute, often recurrent reaction symptoms, which may be recurrent, may examination are essential if a specific diagnosis affecting mucocutaneous tissues, seen precede the onset of the mucosal membrane is required. ulcerations by 6 months to 5 years. A history of especially in younger males. repeated sore throats, tonsillitis, myalgias, and The aetiology of erythema Management migratory erythralgias without overt arthritis is multiforme (EM) is unclear in most patients, Spontaneous healing can be slow common. but it appears to be an immunological hypersensitivity reaction, leading to sub- and – up to 2 to 3 weeks in minor EM and up to 6 intra-epithelial vesiculation. weeks in major EM. Differential diagnosis There may be a genetic Treatment is thus indicated but This is from a range of other predisposition with associations of recurrent controversial and thus specialist care should be syndromes that can affect the eyes, mouth and EM with various HLA haplotypes. sought. Supportive care is important; a liquid skin – such as various dermatological disorders EM is triggered by a range of diet and intravenous fluid may be and . usually exogenous factors, such as: necessary. should be improved  Infective agents, particularly HSV (herpes- with 0.2% aqueous mouthbaths. Diagnosis associated EM: HAEM) and the bacterium The use of is BS can be very difficult to diagnose Mycoplasma pneumoniae; controversial but minor EM may respond to and there is no single diagnostic investigation.  Drugs such as sulfonamides (eg topical corticosteroids. Patients with major EM, The International Study Group for Behçet’s co-trimoxazole), cephalosporins, such as the Stevens-Johnson syndrome, may Disease (ISGBD) criteria suggest the diagnosis aminopenicillins, and many others; need to be admitted for hospital care. Major be made on clinical grounds alone on the basis  Food additives or chemicals. EM patients should be referred for treatment of RAS plus two or more of: with systemic corticosteroids or other  Recurrent genital ulceration; immunomodulatory drugs. Clinical features  Eye lesions; EM ranges from limited disease  Skin lesions; (Minor EM) to severe, widespread life- Websites and patient information  Pathergy – a >2mm diameter erythematous threatening illness (Major EM). Most patients http://emedicine.medscape.com/ nodule or pustule forming 24–48 hours after (70%) in either form, have oral lesions, which article/1122915-overview http://www.nlm. October 2012 DentalUpdate 595 OralMedicine-UpdatefortheDentalTeam

Pemphigoid variants herpetiformis Acquired epidermolysis bullosa (EBA) Toxic epidermal necrolysis (TEN) Erythema multiforme Linear IgA disease

Chronic bullous dermatosis of childhood Figure 6. pemphigoid. Table 1. Uncommon sub-epithelial vesiculobullous disorders.

Figure 5. Pemphigoid. nih.gov/medlineplus/ency/article/000851. htm Mucous membrane pemphigoid is an autoimmune type of disorder with a Pemphigoid genetic predisposition. The precipitating Pemphigoid is the term given event is unclear in most cases but rare cases to a group of uncommon sub-epithelial Figure 7. Pemphigoid, desquamative . are drug-induced (eg by furosemide or immunologically-mediated vesiculobullous penicillamine). disorders (SEIMD) which can affect stratified It is characterized squamous , characterized by immunologically by deposition of IgG and damage to one of the protein constituents Diagnosis C antibodies directed against the epithelial of the basement membrane zone (BMZ) 3 The oral lesions of pemphigoid basement membrane zone (BMZ). There anchoring filament components; a number of may be confused clinically with pemphigus, are also circulating auto-antibodies to BMZ other sub-epithelial vesicullobullous disorders or occasionally erosive lichen planus, components, present in hemi- may produce similar clinical features (Table 1). erythema multiforme or sub-epithelial or the lamina lucida. The main types of pemphigoid that blistering conditions shown in Table 1. The antibodies damage the involve the mouth are: Biopsy of perilesional tissue, with BMZ and histologically there is a sub-basilar  Mucous membrane pemphigoid (MMP), in histological and immunostaining examination split. The pathogenesis probably includes which mucosal lesions predominate but skin can therefore be essential to the diagnosis. complement mediated sequestration of lesions are rare; leukocytes with resultant cytokine and  Oral mucosal pemphigoid – patients with Management leukocyte enzyme release and detachment of oral lesions only, without a progressive Spontaneous remission is rare, the basal cells from the BMZ. ocular scarring process and without serologic and thus treatment is indicated. Specialist reactivity to (BP) antigens; advice is usually needed.  Bullous pemphigoid (BP) – which affects Clinical features Systemic manifestations must mainly the skin; The oral lesions (Figures 5, 6 and be given attention. For that reason, an  Ocular pemphigoid – which is sometimes 7) affect especially the gingivae and consultation is essential to termed cicatricial pemphigoid (CP) since it may and include bullae or vesicles which are tense, rule out occult ocular disease. cause serious conjunctival scarring. may be blood-filled and remain intact for The majority of cases respond However, most of the literature has several days. Persistent irregular erosions or well to topical corticosteroids such as are failed to distinguish these variants, since their ulcers appear after the blisters burst and, if used for aphthae (Article 1). Non-steroidal distinction has only recently been recognized, on the gingivae, can produce desquamative immunosuppressive agents, such as and therefore the following discussion groups gingivitis – the most common oral finding. tacrolimus, may be needed if the response to them together. This is characterized by erythematous, topical corticosteroids is inadequate. ulcerated, tender gingivae in a patchy, rather Severe pemphigoid may need to Mucous membrane/oral pemphigoid than continuous distribution. be treated with using Mucous membrane pemphigoid The majority of people with MMP or systemic corticosteroids. (benign mucous membrane pemphigoid) is an have only oral lesions but genital involvement uncommon chronic disease, twice as common can cause great morbidity and untreated Website and patient information in females, and presenting usually in the fifth to ocular involvement can lead to blindness. http://www.dent.ucla.edu/pic/ sixth decades. Nasal, laryngeal and skin blisters are rare. members/MMP/

596 DentalUpdate October 2012 OralMedicine-UpdatefortheDentalTeam

Variant Oral lesions Main antigens (Ags) Localization Ags Antibodies

Pemphigus vulgaris Common Dsg 3 Desmosomes IgG localized to mucosae (Mucosal)

Pemphigus vulgaris also Common Dsg 3 Desmosomes IgG involving skin/other Dsg 1 mucosae (Mucocutaneous)

Table 2. Main types of pemphigus involving the mouth.

Pemphigus biopsy of perilesional tissue, with histological Differential diagnosis of oral Pemphigus is a group of, and immunostaining examination, are crucial. ulceration fortunately rare, potentially life-threatening Serum should be collected for titres The most important feature chronic diseases characterized by epithelial which provides an assessment of disease of ulceration is whether the is single, blistering affecting cutaneous and/or activity. multiple or persistent. mucosal surfaces. There are several variants  Multiple non-persistent ulcers are most with different auto-antibody profiles and Management commonly caused by viral infections or clinical manifestations (Table 2) but the main Before the introduction of aphthae, when the ulcers heal spontaneously, type is Pemphigus vulgaris; this includes an corticosteroids, Pemphigus vulgaris typically usually within one week to one month. If this uncommon variant . was fatal, mainly from or is not the case, or if the ulcers clinically do not Pemphigus vulgaris is seen mainly in middle- secondary systemic infections. Specialist care appear to be aphthae, an alternative diagnosis aged and elderly females of Mediterranean, is mandatory. Current treatment, by systemic such as erythema multiforme should be Ashkenazi Jewish or South Asian descent. immunosuppression, usually with steroids, or considered. Pemphigus vulgaris is an azathioprine or mycophenolate mofetil, has  A single ulcer that persists may be caused autoimmune disorder in which there is a fairly significantly reduced the mortality to about by neoplasia such as carcinoma, or by strong genetic background. Rare cases have 10%. chronic trauma, a chronic skin disease such been triggered by medications (captopril, as pemphigus, or a chronic infection such as penicillamine, rifampicin and are the , tuberculosis or a mycosis (deep fungal main offenders), or other factors. Websites and patient information infection). The auto-antibodies are directed http://www.pemphigus.org  Multiple persistent ulcers are mainly caused against stratified squamous epithelial by skin diseases such as lichen planus, desmosomes, particularly the proteins Blood disorders that can cause ulcers pemphigoid or pemphigus, gastrointestinal -3 (Dsg3) and desmoglein-1 (Dsg1) include mainly the leukaemias, associated disease, blood disease, immune defect or (Table 2). Damage to the desmosomes leads to with cytotoxic therapy, viral, bacterial or drugs. loss of cell-cell contact (), and thus fungal infection, or non-specific. Other oral In cases where the diagnosis is intra-epithelial vesiculation. features of leukaemia may include purpura, unclear, or where there is a single persistent gingival bleeding, recurrent , ulcer, specialist referral is usually indicated. Clinical features and candidosis. Pemphigus vulgaris typically runs a may produce chronic course, causing blisters, erosions and soreness or mouth ulcers. A small Diagnosis of oral ulceration ulcers on the mucosae and blisters and scabs proportion of patients with aphthae have Making a diagnosis of the cause for on the skin. Oral lesions are common, may be intestinal disease, such as , oral soreness or ulceration is based mainly on an early manifestation, and mimic those of causing and deficiencies of the history and clinical features. The number, pemphigoid in particular. Blisters rapidly break haematinics, when they may also develop persistence, shape, character of the edge of down to leave erosions seen mainly on the angular stomatitis or . Crohn’s disease the ulcer and the appearance of the ulcer palate, buccal mucosa, lips and gingiva. and may also cause base should also be noted. Ulcers should ulcers. (OFG), which always be examined for induration (firmness Diagnosis has many features reminiscent of Crohn’s on palpation), which may be indicative of To differentiate pemphigus from disease, may also cause ulceration. malignancy. The cervical lymph nodes must be other vesiculobullous diseases, a careful history Miscellaneous uncommon diseases such as examined. and physical examination are important, but erythematosus can cause ulcers. Unless the cause is undoubtedly October 2012 DentalUpdate 597 OralMedicine-UpdatefortheDentalTeam

Agent Use Comments

Benzydamine Rinse or spray every Effective in reducing discomfort hydrochloride 1.5 to 3 hours

Lidocaine Topical 4% solution Also reduces taste sensitivity may ease pain

Carboxymethylcellulose Paste or powder used Available containing Figure 8. HIV-associated ulceration. after meals to protect in Canada and the area Antipodes but no longer in UK or USA local, general physical examination Table 3. Topical agents which may reduce pain from mucosal lesions. is also indicated, looking especially for mucocutaneous lesions, other lymphadenopathy or , since it is crucial Procedure to detect systemic causes such as leukaemia, a systemic background to mouth ulcers  A local should be given although, or HIV infection (Figure 8). include: in a few cases, conscious sedation may also be  Extra-oral features such as skin, ocular, necessary. or genital lesions (suggestive of Behçet’s Biopsy  Make the incisions using a scalpel with a syndrome); purpura, fever, lymphadenopathy, Informed consent is mandatory number 15 blade. , or splenomegaly (which for biopsy, particularly noting the likelihood  Do not squeeze the specimen with forceps may be found in leukaemia), chronic of post-operative discomfort, and the while trying to dissect the deep margin. A cough (suggestive of TB or a mycosis), possibility of bleeding or bruising. Care must suture is best used for this purpose (and also gastrointestinal complaints (eg pain, altered be taken not to produce undue anxiety; to protect the specimen from going down the bowel habits, blood in faeces), weakness, some patients equate biopsy with a diagnosis aspirator). loss of weight or, in children, a failure of . Perhaps the most difficult and  Place the biopsy specimen on to a small to thrive. important consideration is which part of piece of paper before immersing in fixative, to  An atypical history or ulcer behaviour such as the lesion should be included in the biopsy prevent curling. onset of ulcers in later adult life, exacerbation specimen.  Put the specimen into a labelled pot, ideally of ulcers, severe aphthae, or aphthae As a general rule, the biopsy in at least 10 times its own volume of buffered unresponsive to topical steroids. should include lesional and surrounding formalin, and leave at room temperature.  Other oral lesions, especially infections tissue. In the case of ulcerated mucosal  Suture the wound if necessary, using suggestive of HIV/AIDS (candidosis, herpetic lesions, most histopathological information resorbable sutures (eg Vicryl). lesions, necrotizing gingivitis or periodontitis, is gleaned from the peri-lesional tissue since, hairy or Kaposi’s sarcoma), by definition, most epithelium is lost from Management of oral ulceration glossitis or angular (suggestive of the ulcer itself. The same usually applies for a deficiency state), or petechiae or gingival skin diseases affecting the mouth, where the  Treat the underlying cause; bleeding or swelling (raising the possibility of epithelium in the area mainly affected will,  Remove aetiological factors; leukaemia). more often than not, separate, and results will  Prescribe a chlorhexidine 0.2% ; Investigations which may be compromised. In the case of a suspected  Maintain good oral hygiene; sometimes be indicated include: potentially malignant or malignant lesion,  A mouthwash or spray or  Blood tests to exclude deficiencies, any red area should ideally be included other topical agents (Table 3) may help ease leukaemia or HIV infection; in the specimen. In some cases where no discomfort.  Microbiological and serological obvious site can be chosen, vital staining with investigations to exclude infection; ‘toluidine blue’ may first be indicated. Referral of patients with oral  Biopsy; A biopsy punch has the ulceration  Immunological studies to exclude skin advantage that the incision is controlled, an Patients with single ulcers diseases and HIV; adequate specimen is obtained (typically persisting more than 3 weeks, indurated ulcers,  Imaging to exclude TB, deep mycoses, 4mm or 6mm diameter) and suturing or multiple persistent ulcers may benefit from a carcinoma, or . may not be required. However, in the skin specialist opinion. disorders, the punch can sometimes split Patients with recalcitrant ulcers, the epithelium or detach it from the lamina or a systemic background to mouth ulcers, or Patients to refer: propria. When a scalpel is used, a specimen needing investigation, may also benefit from a Patients with conditions of elliptical shape is usually taken, most specialist referral. discussed in this section should be referred commonly from an edge of the lesion. Features that might suggest for specialist care. 598 DentalUpdate October 2012