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AN OVERVIEW OF VESICOBULLOUS CONDITIONS AFFECTING THE EMMA HAYES, STEPHEN J CHALLACOMBE Prim Dent J. 2016; 5(1):46-50

in the , buccal mucosa and labial ABSTRACT mucosa there is an underlying . The is formed of several layers, Vesicobullous diseases are characterised by the presence of vesicles or bullae at the deepest being the layer of progenitor varying locations in the mucosa. The most common occurring in the oral cavity cells forming the stratum germinativum, are (MMP) and vulgaris (PV). Both adjacent to the . are autoimmune diseases with a peak age onset of over 60 years and females increase in size and flatten are more commonly affected than men. This paper reviews the structure of the as they move through the oral mucosa, with specific reference to the zone, as well and stratum granulosum to the stratum as bullous conditions affecting the mucosa, including PV and pemphigoid, their corneum (in keratinized mucosa) where the aetiology, clinical presentation, and management. desmosomes, which hold the cells together, weaken – therefore allowing normal Learning outcomes desquamation. • Understand the common presentation of vesicobullous diseases. • Appreciate the role of investigations in diagnosis and its interpretation. In addition to desmosomes, epithelial • Appreciate the roles of both primary and secondary care in patient management. cell-cell contact occurs via occludens (tight junctions), and nexus junctions (gap junctions), with each having a complex structure. Desmosomes are small adhesion Introduction proteins (0.2µm) 1 which guarantee the Vesicobullous diseases are characterised by integrity of the epidermis by linking the the presence of vesicles or bullae at varying intermediate filaments within cells to the locations in the mucosa. They often affect plasma membrane as well as adjacent both the skin and oral mucosa, but can on cells, therefore functioning both as an occasion affect only oral mucosae. The adhesive complex and as a cell-surface most common of the vesicobullous diseases, attachment site for the intermediate which occur in the oral cavity are PV and filaments of the cytoskeleton. Desmosomes MMP. Both are antibody-mediated contain a series of proteins; of particular autoimmune diseases but the target interest with regard to bullous diseases antigens of these two diseases are different. are the desmogleins. The oral and skin In MMP, blisters form owing to antibodies epithelium both express desmoglein 3 binding to components of the basement (DSG3) and desmoglein 1 (DSG1) within membrane zone (BMZ) and in PV to desmosomes, but in the oral mucosa DSG3 KEYWORDS molecules on the surface of keratinocytes. is expressed at a much higher level that Bullous, Basement Membrane Zone, The aetiology, pathology, clinical DSG1, 2 which is important in disease , Mucous presentations, and the treatment of these manifestation and antibody detection Membrane Pemphigoid conditions are discussed. It is outside the for diagnosis. 3 scope of this paper to include full details of the infectious causes of bullae, such Between the epithelial cell layers and AUTHORS as those seen in primary herpetic the lamina propria is a complex structure Emma Hayes BDS gingivostomatitis. linking the two layers, known as the BMZ. DCT2 Oral and Maxillofacial , St George’s The 1-2µm thick 4 BMZ (Figure 1) consists Hospital, London and Department of Oral Medicine, Guy’s and St Thomas’ Hospital NHS The structure of the of the basal cell plasma membrane, the Foundation Trust and King’s College London. oral mucosa lamina lucida, the lamina densa, and the

Stephen J Challacombe PhD, The oral mucosa is a specialised stratified sub-lamina densa. On the epithelial surface FDSRCSE, FDSRCS, FRCPath, FMedSci, DSc, FKC squamous epithelium, which is keratinized of the plasma membrane of the basal Department of Oral Medicine, Guys & St Thomas in areas of high friction (dorsal , keratinocytes are small electron-dense Hospitals NHS Foundation Trust and King’s College 5 London Dental Institute, London. palate, and gingiva), with an underlying domains called hemidesmosomes. These layer (lamina propria); are specialised, multiprotein complexes

46 PRIMARY DENTAL JOURNAL Figure 1: The basement membrane zone linking epithelial cells to the connective tissue that contribute to the attachment of presentation have a 22% risk of developing epithelial cells to the underlying BMZ. them over five years. 9 Nasal involvement A number of proteins that are implicated may present as bleeding or crusting, in the pathogenesis of subepithelial or laryngeal involvement as hoarseness subepidermal blistering diseases such or dysphagia, and genital involvement as MMP are associated with the as painful erosions. hemidesmosomes (such as BP230 and BP180). 6 The second variant presents with desquamative and involves only The lamina lucida consists of laminins the gingivae around the teeth. The gingivae (adhesive glycoproteins which contribute are highly erythematous and hyperaemic to cell adhesion as well as cell migration (Figure 3), and small bullae may be formed and organisation) and is 20–40nm thick. in protected areas around the teeth. This Anchoring filaments transverse the lamina needs to be differentiated from more lucida perpendicularly from the basal cell common causes of membrane to the underlying lamina densa, such as . It is distinct from Illustration by BS Bhogal which contains heparin sulphate coated plaque-induced gingivitis in that it extends type IV . beyond the marginal gingivae; as it is antibody-mediated it will not resolve with Mucous Membrane improvements in , and these Pemphigoid patients therefore require referral to Pemphigoid comprises of an uncommon secondary care for diagnosis and heterogeneous group of disorders – management. including MMP and linear IgA disease – characterised by subepithelial separation Diagnosis and deposition of autoantibodies and Diagnosis is confirmed with a complement along the basement membrane and immunofluorescence. Histologically, zone. MMP is distinguished from skin subepithelial bullae are seen, with no bullous pemphigoid by its predilection acantholytic cells, and the epithelium for mucosal sites and the tendency to form tends to detach itself from the underlying scars, leading to oesophageal strictures, lamina propria. laryngeal stenosis, and blindness in extreme cases of conjunctival cicatrisation. 7 Most cases are detected after the fifth decade, with a mean age of 62, 8 and the disease is more frequent in women than in men.

Intraorally two variants of MMP are seen. The most common manifests as bullous lesions or, more commonly, ulceration involving much of the non-keratinized and occasionally the keratinized mucosa; these are subepithelial, may be blood-filled (Figure 2), and last longer (up to several days) than those seen in PV (see Table 1). Irregular erosions or ulcers can be seen after the bullae burst. Bullous lesions can also involve the conjunctiva, nose, larynx, , oesophagus, genitals, and anus. The oral lesions usually heal without scarring unlike those of the conjunctiva; ophthalmological assessment is therefore important in patients presenting with Figure 2: Irregular oral ulceration in the Figure 3: Desquamative pemphigoid (those without ocular signs at buccal mucosa of a patient with MMP gingivitis in MMP

VOL. 5 NO. 1 FEBRUARY 2016 47 AN OVERVIEW OF VESICOBULLOUS CONDITIONS AFFECTING THE ORAL MUCOSA

those with both circulating IgA and IgG to Pemphigus vulgaris BMZ are associated with more persistent PV is a potentially lethal, chronic, bullous disease. 12 A further group has circulating disease of the stratified squamous mucosa IgG antibodies that bind to the dermal side and skin, which commonly affects the oral of salt-split skin and recognise laminin 5. mucosa and may initially present orally. More than 90% of patients may have Treatment oral lesions at some stage of the disease. If the disease is confined to the In the UK it occurs mainly in adults with and with a low severity score, topical a median age of 71 at presentation 14 ; corticosteroids are often adequate to it is rarely observed in children and control the lesions. In the more severe adolescents. 15 cases, however, and if there is involvement of other sites, systemic corticosteroids may Clinically, PV can present as painful, be needed. In order to keep the steroid fragile, fluid-filled blisters, which may dose to a minimum and reduce steroid- appear on any areas of the oral mucosa related side effects, such as increased and burst within a few hours; as a result, susceptibility to infections, , clinical examination often only reveals Figure 4: Intraoral PV showing irregular osteoporosis and hypertension, an shallow ulcers or erosions (Figure 4). ulceration of the dorsum of the tongue immunosuppressant such as azathioprine Clinically there should be little difficulty or dapsone can also be used. MMP is a in differentiating lesions from recurrent chronic disease, which persists, often with aphthous ulcers as they are large and Immunofluorescence (IMF) is a technique exacerbations and remissions, over many erythematous with irregular outlines and which uses fluorescently-labelled years. Disease severity as well as response are persistent ulcers, not recurrent with antibodies to identify bound to therapy can be monitored by oral onset in middle age rather than in teens autoantibodies. In diagnosing bullous disease severity scoring, 13 a system which as with recurrent aphthous (RAS). conditions both direct and indirect IMF is helpful in both indicating whether local These persist for weeks or months, but are used. Direct IMF uses the biopsy or systemic therapy is needed as well as new lesions recur throughout the disease sample, and the location of the fluorescent monitoring therapeutic responses. Active process. Only occasionally is the Nikolsky labels attached to the autoantibody is vesicobullous conditions can make sign helpful – rubbing the mucosa to noted, for example at the BMZ in MMP. maintenance of good oral hygiene more induce a bulla – as this is also seen in In addition, the type of antibody can also challenging for the patient at home, due other bullous conditions such as MMP. be established; in MMP, Immunoglobulin to discomfort with brushing. However, it Oral manifestations of the disease may G (IgG), Immunoglobulin A (IgA), or is vital that oral hygiene is maintained, persist for many months, without overt ill Immunoglobulin M (IgM), with or without with assistance from their general dental health, but skin lesions (often found on the complement, are found to bind to the practitioner, to prevent caries and chest, face or back), malaise, and loss basement membrane. Recent developing. of weight may occur at a later stage. immunopathological and immunochemical techniques have revealed that MMP In view of the serious and potentially consists of several distinct subgroups fatal nature of PV, due to dehydration based on the specificity of antibodies. or infection, if not treated, it must be The largest subgroup target is BP180. 10 diagnosed correctly and treated in an It is not clear whether the molecular appropriate setting. Diagnosis is again heterogeneity of BP antigens or their via mucosal biopsy and IMF. recognition by IgG and IgA isotypes is Histologically there is acantholysis responsible for the varied clinical (separation and rounding of the presentations. Among the clinical keratinocytes owing to disruption of the subgroup with pure ocular disease, IgA cell-cell adhesion molecules such as antibodies may target an uncharacterised desmosomes) with intraepithelial bulla -derived 45 kD antigen. formation, as well as a leucocytic infiltrate in the lamina propria (Figure 5). Serum Indirect IMF uses the patient’s serum to IgG, IgM, or sometimes IgA detect circulating antibodies, which can Figure 5: Histopathology of blister autoantibodies to desmogleins in skin and bind to normal mucosa. Around 90% of formation in the mucosa and acantholysis mucosa are found in nearly all cases of patients with mucosal disease alone have (rounding of epithelial cells and pemphigus on indirect IMF, and IgG IgG antibodies 11 to the BMZ in their sera, separation from each other) in PV bound to intercellular areas of the

48 PRIMARY DENTAL JOURNAL TABLE 1 KEY DIFFERENCES BETWEEN PEMPHIGUS VULGARIS AND MUCOUS MEMBRANE PEMPHIGOID

Pemphigus vulgaris Mucous membrane pemphigoid epithelium on direct IMF. Antibodies Peak age of onset 65-75 55-65 against DSG3 are found in oral disease, 16 Sites involved Mouth and skin Mouth, eyes, oesophagus whereas antibodies against DSG1 are Target proteins Desmoglein 3 Laminin 5 and BP180 predominant in skin disease. The Site of target proteins Desmosomes Basement membrane autoantibody titre is generally correlated hemidesmosomes with the severity of pemphigus, 17 and as Site of bullae Intraepithelial Subepithelial the lesions heal with treatment, circulating antibodies usually decrease. Antibodies to Prognosis Potentially fatal if Indolent, not fatal widespread and untreated pemphigus antigens can also be detected in , 18 although at present this is not Key clinical features Friable blisters, often Scar formation, tense blisters not seen can last days routinely tested for. PV has a genetic background with HLA class II allele associations found with HLA-DR4 (DRB1*0402) 19,20 and DQB1*0503. 21 may develop the side effects of steroid These HLA class II alleles appear critical therapy (such as adrenal suppression, to T lymphocyte recognition of DSG3 impaired glucose metabolism, peptides and antibody production. osteoporosis, and glaucoma).

Treatment Immunosuppressive therapy using This is usually with systemic corticosteroids azathioprine is usually effective and such as prednisolone in doses of 40-60 allows lower doses of systemic steroids mg/day initially, and is gradually reduced to be used. Local therapy with steroid to the minimal dose that will prevent (eg, Betnesol) is usually formation of new lesions; again a helpful adjunct therapy, and especially immunosuppressant may also be used useful when the clinical disease is under to control the disease and reduce the control and the circulating antibody titre required steroid dose. Treatment with has dropped. Oral disease severity corticosteroids has completely changed scores 13 are helpful in assessing both the prognosis of the disease. Steroids may the presenting disease severity and the need to be maintained for life, but clinical response to treatment. improvement, along with reduction in circulating antibody titre, allows the dose Other forms of pemphigus to be reduced to minimal levels. Patients Another important form of pemphigus rarely die now from the disease but they affecting the oral mucosa is

REFERENCES Mosby/Elsevier; 2009. 10 Oyama N, Setterfield J, Powell A, with IgG and IgA signifies a more 5 Katz SI. The epidermal basement SakumaOyama Y, Albert S, Bhogal B, severe and persistent disease. Br J 1 McMillan JR, Shimizu H. Desmosomes: membrane zone—structure, ontogeny, et al. Bullous pemphigoid antigen II Dermatol 1998; 138 (4):602-610. structure and function in normal and and role in disease. J Am Acad (BP180) and its soluble extracellular 13 Escudier M, Ahmed N, Shirlaw P, diseased epidermis. J Dermatol Dermatol. 1984; 11 (6):1025-37. domains are major autoantigens in Setterfield J, Tappuni A, Black MM, 2001; 28 (6):291-98. 6 Borradori L, Sonnenberg A. Structure mucous membrane pemphigoid: the Challacombe SJ. A scoring system for 2 Shirakata Y, Amagai M, Hanakawa Y, and function of hemidesmosomes: pathogenic relevance to HLA class II mucosal disease severity with special Nishikawa T, Hashimoto K. Lack of more than simple adhesion complexes. alleles and disease severity. Br J reference to oral lichen planus. Br J mucosal involvement in pemphigus J Invest Dermatol. 1999; 112 (4):411-18. Dermatol 2006; 154 (1):90-8. Dermatol 2007; 157 (4):765-70. foliaceus may be due to low 7 Foster CS. Cicatricial pemphigoid. 11 Kelly SE, Wojnarowska F. The use of 14 Langan SM, Smeeth L, Hubbard R, expression of desmoglein 1. J Invest Trans Am Ophthalmol Soc. chemically split tissue in the detection Fleming KM, Smith CJ, West J. Bullous Dermatol 1998; 110 (1):76-8. 1986; 84 :527-663. of circulating antibasement membrane pemphigoid and pemphigus vulgaris-- 3 Hashimoto T. Recent advances in 8 Ahmed AR, Hombal SM. Cicatricial zone antibodies in bullous pemphigoid incidence and mortality in the UK: the study of the pathophysiology pemphigoid. Int J Dermatol. and cicatricial pemphigoid. Br J population based cohort study. BMJ of pemphigus. Arch Dermatol Res 1986; 25 (2):90-6. Dermatol 1988; 118 (1):31-40. 2008; 9;337:a180. 2003; 295 (1):S2-S11. 9 Thorne JE, Anhalt GJ, Jabs DA. 12 Setterfield J, Shirlaw PJ, Kerr-Muir M, 15 Ariyawardana A, Tilakaratne WM, 4 Berkovitz BK, Holland GR, Moxham Mucous membrane pemphigoid and Neill S, Bhogal BS, Morgan P, et al. Dissanayake M, Vitanaarachchi N, BJ. Oral anatomy, and pseudopemphigoid. Ophthalmology. Mucous membrane pemphigoid: a Basnayake LK, Sitheeque MA, et al. embryology. Edinburgh: 2004; 111 (1):45-52. dual circulating antibody response Oral pemphigus vulgaris in children

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paraneoplastic pemphigus (most potentially fatal forms can occur Epidermolysis bullosa commonly associated with haematological ( major). Epidermolysis bullosa represents a group malignancies), 22 as oral lesions have been of bullous diseases, which can be either seen in all reported cases of The aetiology of oral EM has not been inherited or the acquired autoimmune paraneoplastic pemphigus and may be the established, but many agents have been form (epidermolysis bullosa acquisita). first or sole manifestation. Paraneoplastic implicated including drugs (allopurinol, It predominantly affects the skin, but pemphigus should be suspected if antibiotics, anticonvulsants, and NSAIDs) there may also be mucosal involvement. assumed PV does not respond to therapy. and viruses (particularly herpes type 1 The inherited form may also show dental This form usually improves with treatment and 2, and Mycoplasma pneumoniae); 23 abnormalities such as pitting hypoplasia of the underlying malignancy. Other types recurrent EM is almost always associated or thin enamel. 25 Clinical presentation of pemphigus such as pemphigus foliaceus with virus (HSV), although can vary, with bullae at the intraepithelial rarely affect the oral mucosa as the target it is not usually isolated from the lesions level, BMZ, or subepithelial depending antigen is DSG1. In pemphigus vegetans, or demonstrable in biopsy specimens. on the type. The subepithelial forms result vegetation type lesions may be found in scarring, which can result in stricture on the oral mucosa and , and Diagnosis is based on clinical signs formation, and histological examination shows and histology; there are degenerative . 26 Treatment of epidermolysis intraepithelial abscesses containing changes at the dermoepidermal junction bullosa acquisita is traditionally with numerous eosinophils. and acanthosis, with either subepithelial immunosuppression or, more recently, or intraepithelial bullae. The degenerating with intravenous immunoglobulins. 27 Erythema multiforme oral epithelium is strikingly eosinophilic, Erythema multiforme (EM) is an and there is a lymphohistiocytic Summary uncommon, mucocutaneous disease infiltration in the lamina propria. The wide variety of vesicobullous characterised by symmetrical skin target diseases, with their associated morbidity lesions, particularly of the extremities, There is no specific treatment for EM, and mortality mean that early diagnosis with oral or other mucosal involvement although corticosteroids are often used, at a specialised centre (such as oral in some cases, and a marked tendency either topically in mild disease or medicine or dermatology) is vital, if to recur. Mucosal involvement may systemically in more severe disease, potential sequelae are to be avoided. precede or follow skin lesions and is as well as supportive management As most of these conditions present commonly found without skin lesions. such as intravenous fluids and analgesia. initially with oral lesions, it is imperative The condition mainly affects young adult In recurrent EM, antivirals such as that general dental practitioners refer all men and it is most commonly found in acyclovir may be used to suppress suspected cases for further investigation. the mild form, but more severe and disease recurrence. 24

and adolescents: a review of the autoantibodies in saliva and response is linked to HLA-DQB10503 in recurrent erythema multiforme. literature and a case report. Int J of comparison with serum values. Eur J in Pakistani patients. Hum Immunol Br J Dermatol 1995; 132 (2):267-70. Paediatr Dent 2005; 15 (4):287-93. Oral Sci 2006; 114 (5):374-80. 1997; 57 (2):110-9. 25 Wright JT, Johnson LB, Fine JD. 16 Challacombe SJ, Setterfield J, Shirlaw 19 GonzálezEscribano MF, Jimenez G, 22 Kaplan I, Hodak E, Ackerman L, Developmental defects of enamel in P, Harman K, Scully C, Black MM. Walter K, Montes M, PerezBernal Mimouni D, Anhalt GJ, Calderon S. humans with hereditary epidermolysis Immunodiagnosis of pemphigus and AM, Rodríguez MR, et al. Distribution Neoplasms associated with bullosa. Arch Oral Biol mucous membrane pemphigoid. Acta of HLA class II alleles among Spanish paraneoplastic pemphigus: a review 1993; 38 (11):945-55. Odontol Scand 2001; 59 (4):226-34. patients with pemphigus vulgaris. with emphasis on non-hematologic 26 Wright JT, Fine JD, Johnson LB. Oral 17 Harman KE, Seed PT, Gratian MJ, Tissue Antigens 1998; 52 (3):275-8. malignancy and oral mucosal soft tissues in hereditary epidermolysis Bhogal BS, Challacombe SJ, Black 20 Mobini N, Yunis EJ, Alper CA, Yunis JJ, manifestations. Oral Oncol bullosa. Oral Surg Oral Med Oral MM. The severity of cutaneous and Delgado JC, Yunis DE, et al. Identical 2004; 40 (6):553-62. Pathol 1991; 71 (4):440-6. oral pemphigus is related to MHC markers in non-Jewish Iranian 23 Huff JC, Weston WL, Tonnesen MG. 27 Segura S, Iranzo P, Martínez-de Pablo desmoglein 1 and 3 antibody levels. and Ashkenazi Jewish patients with Erythema multiforme: a critical review I, Mascaró JM, Alsina M, Herrero J, Br J Dermatol 2001; 144 (4):775-80. pemphigus vulgaris: possible common of characteristics, diagnostic criteria, et al. High-dose intravenous 18 Andreadis D, Lorenzini G, Drakoulakos central Asian ancestral origin. Hum and causes. J Am Acad Dermatol immunoglobulins for the treatment of D, Belazi M, Mihailidou E, Velkos G, et Immunol 1997; 57 (1):62-7. 1983; 8(6):763-75. autoimmune mucocutaneous blistering al. Detection of pemphigus desmoglein 21 Delgado JC, Hameed A, Yunis JJ, 24 Tatnall FM, Schofield JK, Leigh IM. diseases: evaluation of its use in 19 1 and desmoglein 3 autoantibodies Bhol K, Rojas AI, Rehman SB, et al. A doubleblind, placebocontrolled cases. J Am Acad Dermatol and pemphigoid BP180 Pemphigus vulgaris autoantibody trial of continuous acyclovir therapy 2007; 56 (6):960-7.

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