Mucocutaneous diseases affecting the oral cavity are predominantly immune mediated or inflammatory. Three of the most common and clinically significant conditions are reviewed in this article: lichen planus, pemphigus vulgaris, and mucous membrane pemphigoid. Because oral manifestations may be the first or only manifestation of mucocutaneous diseases, oral health professionals play a critical role in the early diagnosis and multidisciplinary management of these conditions.
Key points
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Oral manifestations of mucocutaneous diseases may be the first, only, and/or most significant sign of disease.
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Although some clinical features are pathognomonic for a specific disease, others are nonspecific. Diagnostic tests, including histopathology and immunofluorescence studies, are crucial in achieving a definitive diagnosis.
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Because of the systemic nature of mucocutaneous diseases, a multidisciplinary approach in management is necessary.
Introduction
The oral mucosa originates in large part from an invagination of the ectoderm and is therefore comparable with the skin. Both structures are composed of highly specialized stratified squamous epithelium, mainly comprising keratinocytes adhering to one another and to the underlying basement membrane and connective tissue. Mucocutaneous conditions are a group of disorders mostly confined to the epithelium, thereby involving the skin and oral mucosa. Other mucosal sites, such as genital mucosa, nasal mucosa, and conjunctiva, are also affected.
Oral mucosal manifestations vary and may be the initial feature, most prevalent and/or symptomatic feature, or only sign of disease. Although mucocutaneous disorders are mainly observed in the dermatology practice, a multidisciplinary approach is critical for effective care. Based on the clinical presentation, the dental practitioner may be the first to identify oral lesions and hence plays an important role in the early diagnosis and management of disease.
Mucocutaneous disorders can be broadly categorized based on cause into developmental (genodermatoses), infectious, inflammatory, immune-mediated or autoimmune, and neoplastic conditions. These diseases are autoimmune/immune mediated or inflammatory, and are characterized by frequent and early involvement of the oral mucosa. This article discusses the more common and clinically significant mucocutaneous conditions and provides overview information on less common conditions ( Box 1 ).
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Most common
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Lichen planus
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Pemphigus vulgaris
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Mucous membrane pemphigoid
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Less common
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Erythema multiforme
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Systemic lupus erythematosus
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Epidermolysis bullosa
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Psoriasis
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Chronic ulcerative stomatitis.
Lichen planus
Epidemiology
Lichen planus (LP) is a chronic inflammatory disorder that most frequently involves the skin and/or oral mucosa. Compared with cutaneous disease, oral LP (OLP) tends to be more chronic, with a mean age at onset in the fifth to sixth decades and a slight female predilection. Data on the prevalence of OLP are limited, with estimates ranging between less than 1% and up to 3% of the population, making OLP the most common mucocutaneous condition in the mouth.
Pathobiology
OLP is considered a T cell–mediated reaction directed against epithelial basal cells, but the target antigen, whether endogenous or exogenous, is unknown. Following antigen recognition, both cluster of differentiation (CD) 4+ T-helper cells and CD8+ cytotoxic T cells are activated, with a predominance of CD8+ cells within the epithelium. The exact mechanism of the ensuing basal keratinocytes apoptosis remains unknown; however, it is thought to be triggered by granzyme B release, tumor necrosis factor alpha secretion, and Fas Ligand expression. Aside from these antigen-specific processes, the development of OLP also is thought to involve mast cell degranulation and matrix metalloproteinase activation, leading to basement membrane disruption and migration of lymphocytes through the epithelium.
Several causal factors have been implicated in OLP, including (1) psychological stress; (2) local and systemic inducers of cell-mediated hypersensitivity; and (3) infectious agents. Acute exacerbations of OLP have been linked to psychological stress, and anxiety and depression are reported to be more common in patients with OLP compared with normal controls. Lichenoid mucositis is an umbrella term for lichenoid hypersensitivity reactions, presenting with clinical and histologic features almost identical/very similar to OLP. Oral lichenoid contact lesions (OLCLs) are typically triggered by dental restorative materials (mainly amalgam) or food flavoring (usually cinnamic aldehyde). Oral lichenoid drug reactions (OLDRs) arise in temporal association with exposure to certain medications, such as oral hypoglycemic agents, diuretics, angiotensin-converting enzyme inhibitors, or nonsteroidal antiinflammatory drugs. Strong evidence suggests an association between hepatitis C virus (HCV) infection and OLP in some geographic regions, such as southern Europe and Japan. The mechanism underlying this association is not clear but may be related to a pattern of immune dysregulation and could involve a cytotoxic immune response to epithelial cells infected with HCV.
Clinical Presentation
Classic cutaneous LP presents with violaceous papules, sometimes polygonal, and often covered by a network of fine white lines (Wickham striae). Lesions appear mainly on the flexural aspect of the wrists and ankles and in the lumbar region. They are characteristically pruritic and self-limiting, remitting within 1 to 2 years in most cases.
Although up to 60% of patients with cutaneous LP may show oral disease, only 15% of patients with OLP develop cutaneous lesions. In these cases, lesions develop within several months after the appearance of oral disease. OLP is characterized by roughly symmetric and bilateral distribution, typically affecting the buccal mucosa, gingiva, and/or tongue. This characteristic distribution allows differentiation of OLP from OLCLs ( Table 1 ). Although histopathologically similar to OLP, OLCLs are often unilateral in presentation, occurring in direct topographic relationship with the offending agent ( Fig. 1 ).
| Entity | Common Clinical Presentation | Typical Histopathology | Characteristic Immunofluorescence Findings |
|---|---|---|---|
| OLP |
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| OLCLs |
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| OLDRs |
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| Mucous membrane pemphigoid |
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| LP pemphigoides |
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| Pemphigus vulgaris |
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| Chronic graft-versus-host disease |
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|
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| Lupus erythematosus |
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|
|
OLP can be classified into 6 subtypes based on clinical appearance. These subtypes may present individually or concurrently: reticular, atrophic, erosive, papular, plaque, and bullous. A more recent classification groups lesions into only 3 clinical subtypes: reticular, atrophic/erythematous, and ulcerative ( Table 2 , Fig. 2 ). By far, the reticular subtype is the most common, presenting with Wickham striae, and is generally asymptomatic. Atrophic and ulcerative forms are usually accompanied by reticulation, facilitating the differentiation process from other mucocutaneous diseases, such as pemphigus vulgaris or mucous membrane pemphigoid (MMP). When affecting the gingiva, atrophic OLP often presents as desquamative gingivitis, with painful diffuse erythema, erosion, and desquamation of the attached and marginal gingiva. Although OLP is the leading cause, other mucocutaneous disorders can lead to desquamative gingivitis and these cases can be clinically indistinguishable ( Box 2 ).
| Type | Clinical Appearance and Common Sites | Comments |
|---|---|---|
| Reticular | White striations (Wickham striae), papules, or plaquelike lesions on the buccal mucosa, ventral and dorsal tongue, labial mucosa, or gingiva. Usually asymptomatic | Most common manifestation of disease |
| Atrophic | Areas of erythema, particularly on the gingiva (desquamative gingivitis). May be painful | Usually in conjunction with reticular lesions |
| Ulcerative | Ulcerations, rare bullae. May cause significant pain | In conjunction with reticular and erythematous lesions |
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OLP and lichenoid lesions
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Vesiculobullous diseases
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Mucous membrane pemphigoid
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Pemphigus vulgaris
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Less common: paraneoplastic pemphigus, epidermolysis bullosa acquisita, and linear immunoglobulin A disease
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Plasma cell gingivitis
When more than 1 site is concurrently involved, the severity of the oral disease does not necessarily correlate either with the extent of involvement or with the severity of the disease in the other sites. Furthermore, the intensity of symptoms in the oral cavity is variable and, in some cases, symptoms are expressed only when triggered by spicy or acidic foods. A sense of mucosal roughness or reduced mucosal flexibility may also be noted.
Diagnosis and Assessment
Definitive diagnosis of OLP relies on both clinical and histopathologic features. The clinicopathologic correlation is especially important considering the various OLP mimics that may present with similar clinical and/or histopathologic characteristics (see Table 1 ).
Histopathology
The 2003 modified World Health Organization (WHO) diagnostic criteria for OLP outline 2 hallmark features ( Fig. 3 ) :
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A well-defined, bandlike zone of lymphocytic infiltration confined to the superficial lamina propria
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Liquefactive degeneration (squamatization) of the basal cell layer
Other microscopic features include hyperparakeratosis and/or orthokeratosis, acanthosis, sawtooth-rete ridges, and cytoid (colloid or Civatte) bodies. Subepithelial clefting may occur and is a common artifact caused by the weakened basal cell adhesion to the connective tissue.
Immunofluorescence
Tissue diagnosis may be challenging because the histopathologic features of OLP may be influenced by a variety of factors, including the clinical subtype and the severity of disease at the time of the biopsy. The use of direct immunofluorescence (DIF) is thus recommended as a diagnostic adjunct, and can facilitate, for example, the differentiation of OLP from vesiculobullous diseases (see Table 1 ). This differentiation is of particular importance in the case of OLP presenting solely as desquamative gingivitis, or in the rare case of LP pemphigoides of the pemphigoid family, characterized by the development of vesiculobullous lesions on areas affected by LP. DIF requires submission of tissue in Michel solution as opposed to the 10% formalin used to transport tissue for routine hematoxylin-eosin (H&E) staining. To this end, 2 samples should be obtained. OLP is characterized by deposition of fibrinogen in a shaggy pattern along the basement membrane zone (BMZ) with variable deposition of immunoglobulin (Ig) and complement.
Treatment
Management of OLP focuses on symptom alleviation, because no cure exists. Although not specific for OLP, patients benefit from elimination of local factors that may trigger or exacerbate symptoms. These factors may include sharp or rough restorations, ill-fitting dentures, or plaque-induced gingival disease. Oral lichenoid reactions may resolve following identification and removal of the offending agent. Patch testing can further assist in determining alternative materials to use.
Pharmacologic therapy
Although asymptomatic OLP requires no treatment other than periodic observation, symptomatic cases are managed pharmacologically based on the extent and severity of disease. Topical corticosteroids are first-line therapy. The potency of the agent, coupled with the delivery formulation, significantly affect the effectiveness of the treatment ( Table 3 ), and maximal efficacy is ensured by providing the patient with clear instructions for use. For refractory and symptomatic localized ulcerative lesions, intralesional injections of triamcinolone acetonide (10–40 mg/mL) can be used. Alternatively, tacrolimus 0.1%, a calcineurin inhibitor, can be used topically either as an ointment or a compounded solution when topical corticosteroids alone are insufficient. Topical retinoids, tretinoin 0.1% or isotretinoin 0.1%, can also be considered as second-line treatment. Because topical immunosuppressive treatment increases the risk of secondary candidiasis, prophylactic topical or systemic antifungal therapy may be required and should be considered on a case-by-case basis.
| Medication a | Instruction of Use b | Comments |
|---|---|---|
| Topical Gels, Creams, and Ointments | ||
| Clobetasol 0.05% Fluocinonide 0.05% Betamethasone dipropionate 0.05% Triamcinolone 0.1%–0.5% |
Apply to lesions 2–4 times per day. Gels can be applied with gauze and left in place 10–15 min Extensive gingival lesions can be treated with occlusive trays that hold the gel on the affected areas |
Gels are preferred for intraoral use and are effective in managing limited areas of involvement |
| Topical Solutions | ||
| Dexamethasone 0.1 mg/mL (5 mL) Prednisolone 3 mg/mL (5 mL) |
Hold solution and swish in mouth for 4–6 min before expectoration. Repeat 2–4 times per day | For mild to moderate cases in which lesions are diffuse, numerous, or inaccessible to topical application |
a Drugs are listed in a descending order of potency.
b For all cases of topical therapy, patients are instructed to wait 10 to 15 minutes after application before eating/drinking or brushing teeth.
The addition of systemic therapy is considered during acute severe exacerbations of localized disease, or in cases involving extraoral sites as well (eg, genitalia, skin, or esophagus). Systemic prednisone (1 mg/kg/d) is generally effective and should be used for the shortest possible duration in order to mitigate potential adverse effects. If used for longer than 2 weeks, a taper is needed. Evidence to support the use of other, steroid-sparing systemic agents is sparse and generally weak. These agents include hydroxychloroquine, azathioprine, and mycophenolate mofetil.
Prognosis and Monitoring
OLP is a chronic condition, characterized by waxing and waning severity. Patients are typically followed at least annually, with the frequency of follow-up visits increasing proportionally with disease activity and symptoms. The importance of long-term monitoring and periodic repeat biopsy is further emphasized by the reported risk of malignant transformation, especially in the erosive subtype of disease. Depending on the study, the transformation rate varies between 0.4% and 5.8% over periods of observation from 0.5 to more than 20 years. This variability primarily stems from the lack of concordance in the diagnostic criteria of OLP and is at the heart of the controversy surrounding its malignant potential. In a recent attempt to address this problem, Aghbari and colleagues conducted a meta-analysis limited to studies using the modified WHO diagnostic criteria, showing an overall 0.9% transformation rate.
Pemphigus vulgaris
Epidemiology
Pemphigus refers to a group of autoimmune acantholytic blistering disorders that affect the mucosa and skin. Several variants of pemphigus have been described based on clinicopathologic correlation, including pemphigus vulgaris (PV), pemphigus foliaceus, paraneoplastic pemphigus (PNP), and other less common varieties. Only PV and PNP typically have oral involvement. PV is the most common variant, preferentially affecting women in their fifth and sixth decades of life. Showing a strong genetic component, PV is more prevalent in certain ethnic groups, particularly Ashkenazi Jews and individuals of Mediterranean and south Asian origin. The incidence of PV is extremely variable and ranges between 0.5 and 50 cases per million based on the population evaluated.
Pathobiology
Pemphigus is understood to be predominantly familial, although sporadic cases have been reported. Many human leukocyte antigen (HLA) genetic profile studies have been performed and associations have been noted for HLA-DRB1*0402/1401/1404 , DQB1*0503 , and DRB1*03/07/15 in distinct populations, among several others. Although many of these phenotypes have associated risks, the correlation between the HLA status and patients’ clinical outcomes is still vague.
Historically, PV is thought to result from antibody-mediated acantholysis leading to suprabasal blistering. According to the compensation hypothesis, IgG serum autoantibodies are directed against desmogleins (Dsg) 1 and 3, members of the cadherin family of molecules that are present in desmosomes and are normally responsible for maintaining the structural integrity of stratified squamous epithelium. In normal mucosa and skin, these are expressed throughout the thickness of the epithelium with a predominance of Dsg3 in oral mucosa. This differential expression profile of autoantibodies significantly corresponds to the patient’s clinical presentation and extent of mucous membrane and cutaneous involvement. Hence, patients with oral mucosal involvement have chiefly anti-Dsg3 autoantibodies that lead to defective cell adhesion and acantholysis.
Nowadays, it is thought that the pathogenesis of PV is more complex, with factors other than autoantibodies against Dsg1 and Dsg3 contributing to the development of disease. Studies on mechanistic pathways of Dsg antibody generation have led to the identification of a synergistic model formed from a trifecta of autoantibody-guided steric hindrance of Dsg-mediated adhesion, altered desmosome assembly, and altered signaling pathways.
Clinical Presentation
The lesions in PV typically present in a mucocutaneous fashion with extremely rare cases involving only the skin. The oral mucosal lesions are usually the first to appear, followed by mucosal lesions in other sites, such as the larynx, esophagus, conjunctiva, nose, anus and genitals, or the skin. Cutaneous lesions present as flaccid bullae and erosions, commonly presenting on the head, trunk, and groin.
Exclusive oral mucosal involvement is estimated to occur in 50% of cases, consisting of flaccid blisters, painful erosions, and superficial ulcers ( Fig. 4 ). A recent study of 31 cases of PV revealed that nongingival lesions were present more frequently (55% of cases) and desquamative gingivitis was noted in less than a third of the cases. These data are consistent with previous reports of site-specific oral mucosal involvement of PV.
