Excerpt from Oral Manifestations of Autoimmune Blistering Diseases

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Background

Oral lesions are observed commonly in autoimmune blistering skin diseases. Oral lesions can be the predominant or minor clinical manifestation of a given disease. Pemphigus vulgaris and bullous pemphigoid are the earliest recognized autoimmune blistering diseases, and, together, they account for about one half of the autoimmune blistering diseases. While most patients with pemphigus vulgaris have oral lesions, only a few patients with bullous pemphigoid have oral lesions. Over the last few decades, many other autoimmune blistering diseases have been delineated, and some of these newly identified diseases have oral manifestations.

This article discusses the oral manifestations of several well-characterized autoimmune blistering diseases, including pemphigus vulgaris, bullous pemphigoid, linear immunoglobulin A (IgA) bullous dermatosis, and paraneoplastic pemphigus. A group of autoimmune blistering diseases affecting primarily the mucous membrane is termed cicatricial pemphigoid or mucous membrane pemphigoid. Since this topic is discussed in a separate article, Cicatricial Pemphigoid is not described in great detail in this article.

Animal models

Spontaneous animal homologues of human autoimmune blistering diseases have been identified in the last 2 decades.¹ Those diseases in which oral involvement occurs include pemphigus vulgaris (dogs, cats), paraneoplastic pemphigus (1 dog), bullous pemphigoid (dogs, cats, horses, pigs),^{2, 3} mucous membrane pemphigoid (dogs, cats),⁴ linear IgA bullous dermatosis (dogs), epidermolysis bullosa acquisita (dogs), and bullous systemic lupus erythematosus (1 dog). The histopathologic and immunopathologic findings usually are the same as that of human diseases and are not discussed here.

• Pemphigus group: Pemphigus vulgaris is a very rare acantholytic skin disease. In most cases, oral involvement is severe, and the mouth sometimes can be the first site to exhibit lesions. Flaccid vesicles on the gums, tongue, and palate evolve rapidly into erosions and ulcerations with indistinct margins and peripheral sloughing of mucosal epithelium (Nikolsky sign). Pemphigus foliaceus, the most common form of pemphigus observed in animals, affects dogs and cats. It usually does not affect oral and other mucosal membranes.
• Pemphigoid group
• • Bullous pemphigoid: In dogs and cats with bullous pemphigoid, oral involvement is seen in less than 50% of them. When present, mucosal lesions consist of vesicles and sharp-edged erosions and ulcers of the gum. In horses with bullous pemphigoid, mucosal sloughing appears early, and oral ulceration is widespread and severe. By contrast, pigs with bullous pemphigoid do not exhibit oral lesions.
  • Mucous membrane pemphigoid: Dogs and cats with the recently recognized mucous membrane pemphigoid exhibit lesions that predominate at mucosae and mucocutaneous junctions. Tense oral vesicles can occur early in the course of the disease. However, at the time of diagnosis, most animals present with mild-to-severe oral erosions and ulcerations. These lesions occur most commonly on the gum but also occur on the tongue and palate. Lesions occasionally extend to the lips. German shepherd dogs comprise approximately one third of the animals with mucous membrane pemphigoid.
  • Linear IgA bullous dermatosis: Oral lesions were present in 2 dogs with this disease, albeit being of minimum severity.
  • Epidermolysis bullosa acquisita: This disease can be divided into 2 forms. The generalized inflammatory form (seen most commonly in Great Dane dogs) is associated with rapid and extremely severe sloughing of the oral mucosa. The severe oral lesion is associated with anorexia and weight loss and can lead to sepsis. No oral lesions were observed in 1 dog with the localized form.
  • Bullous systemic lupus erythematosus: Ulceration of both the tongue and lips was observed in 1 dog with bullous systemic lupus erythematosus.
• Paraneoplastic pemphigus: The association with thymic lymphosarcoma was documented in the only dog reported to have paraneoplastic pemphigus. Oral lesions in this dog were severe, consisting of mucosal erosions and ulcerations.

Pathophysiology

As a group, autoimmune blistering skin diseases are recognized as autoantibody-mediated diseases. This group of diseases can be divided into 2 major subsets, the pemphigus subset and the pemphigoid subset. Whereas the pemphigus subset of diseases is mediated by autoantibodies that target the extracellular skin components that link one epidermal cell to another, the pemphigoid subset of diseases is mediated by autoantibodies that target the extracellular skin components that link the skin basement membrane components either to the lowermost layer of epidermal cells or to the dermal components. Accordingly, the pemphigus subset of diseases is termed intraepidermal blistering disease, while the pemphigoid subset of diseases is named subepidermal blistering disease. Passive transfer experiments have demonstrated that purified autoantibodies from patients with the pemphigus group of diseases can induce blister formation when delivered to newborn mice.

Passive transfer experiments using autoantibodies from human patients with 2 major forms of the pemphigoid group of diseases (ie, bullous pemphigoid, epidermolysis bullosa acquisita) failed to induce clinically observable blisters in newborn mice; however, rabbit antibodies raised against the recombinant proteins encoded by the gene of mouse bullous pemphigoid antigen 2 (BP180) are capable of inducing blisters in newborn mice in a complement-dependent manner. Furthermore, anti-BP180 autoantibodies from patients affected with BP are capable of inducing dermal-epidermal separation in cryosections of normal human skin, further supporting the pathogenic role of BP180.

In addition, rabbit antibodies raised against type VII collagen (epidermolysis bullosa acquisita antigen) are also capable of inducing blisters in mice. So far, no truly active experimental animal models (in which healthy mice are induced to autoimmune disease de novo) are known to facilitate the studies on the induction phase of autoimmune blistering diseases. Nevertheless, autoantibodies can be induced by immunized healthy BALB/c mice with synthetic peptides of the mouse bullous pemphigoid antigen 2 NC16A domain.

In certain patient subsets, the development of the autoimmune disease has been proposed to have been triggered by an immune phenomenon, "epitope spreading," a concept stating that tissue injuries from an inflammatory event may expose the previously hidden autoantigen to autoreactive lymphocytes, leading to autoimmune disease.^{5, 6} Possible clinical examples include mucous membrane pemphigoid and paraneoplastic pemphigus. For example, patients who developed ocular mucosal injury secondary to an inflammatory disease termed Stevens-Johnson syndrome are noted to subsequently develop ocular mucous membrane pemphigoid.⁷

Frequency

United States

The true frequency at which autoimmune blistering skin diseases occurs in the United States is not known.

International

The true frequency at which autoimmune blistering skin diseases occurs internationally is not delineated. Nevertheless, it is now well recognized that this group of diseases has occurred throughout the world in Europe, Asia, the Americas, and Arabic countries.

Mortality/Morbidity

The pemphigus group of diseases (particularly pemphigus vulgaris) generally is more severe and has higher mortality than the pemphigoid group of diseases. Both the pemphigus and pemphigoid groups of diseases are chronic inflammatory diseases and, therefore, carry significant morbidity from the diseases themselves and the adverse effects of therapeutic medications.

• Pemphigus group: Before the availability of corticosteroids, most patients with pemphigus vulgaris died. The extensively denuded skin surfaces from the broken blisters in these patients made them very susceptible for all kinds of infections, water loss, and electrolyte imbalance. Severe oral erosions interfered with patients' proper eating and drinking and significantly hindered their nutrient intake and the health of their immune functions, thus further reducing their ability to defend against infections. The long-term use of corticosteroids and immunosuppressives introduces significant adverse effects (eg, osteoporosis, diabetes, susceptibility to infections). Several cases of cutaneous squamous cell carcinomas and one case of primary brain lymphoma have been reported to develop in patients with pemphigus vulgaris who received long-term immunosuppressive treatments.⁵
• Pemphigoid group: As a group, a much lower mortality exists for this group than for the pemphigus group of diseases; nevertheless, the chronicity of the diseases can bring significant morbidity to patients. Adverse effects from chronic use of corticosteroids and immunosuppressives also can contribute to morbidity.
• Paraneoplastic pemphigus: This disease is the most resistant to conventional medical treatment. If the primary neoplasm associated with the pemphigus is found and removed completely, patients usually responded to the treatments relatively well and could recover completely; however, if the primary neoplasm is not found or cannot be eradicated completely, the disease will likely lead to a fatal outcome.

Race

No significant racial predilection for autoimmune blistering skin diseases exists other than an increase in frequency of pemphigus vulgaris in some Jewish populations.

Sex

No sexual predilection for autoimmune blistering skin diseases exists other than a slight predilection of females for mucous membrane pemphigoid.

Age

Autoimmune blistering diseases primarily affect elderly patients, although occasional cases of childhood onset have been reported. The noted exception is linear IgA bullous dermatosis; about one half of patients with this disease have onset during childhood.

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