11  Oral Manifestations of Autoimmune, Immune-Mediated, and Allergic Disorders

11.0 INTRODUCTION

An intact immune system is essential for health, and in the context of oral diseases, is critical for the prevention and clearance of infections. Many disorders are characterized by an exaggerated response of the immune system, producing inflammatory or autoimmune reactions that lead to further disease. These conditions can be broadly classified as autoimmune, immune-mediated, and allergic disorders, each being potentially ­associated with oral manifestations. Management of these disorders depends largely on the clinical diagnosis and severity of features, and frequently requires topical and/or systemic immunomodulatory therapies for management. Oral health providers should be aware of the potential oral manifestations of these disorders, as they can be associated with significant morbidity and in some cases may be the initial presenting feature of the disease. This chapter will describe the clinical diagnostic features of the most commonly encountered autoimmune, immune-mediated, and allergic disorders with oral manifestations.

11.1 Autoimmune conditions

Autoimmune diseases result from loss of self-tolerance or an overactive immune response and are characterized by the production of circulating autoantibodies and immune complexes. In addition to autoantibody production by plasma cells, T-cells also play an integral and critical role in the pathogenesis of autoimmune conditions. Approximately 5–8% of the U.S. population has been diagnosed with autoimmune disease, and women are more likely than men to be affected. Diagnosis can be challenging due to a myriad of signs and symptoms that can develop over months to years prior to full disease presentation. The etiology of autoimmune disorders is poorly understood, though it is likely associated with genetic, infectious, and/or environmental factors. Some conditions primarily target epithelium, resulting in vesiculobullous disorders, while others primarily affect connective tissue and are known as collagen vascular diseases. The diagnosis and evaluation of Sjögren syndrome, an autoimmune disease with significant oral considerations, is covered in detail in chapter 8.

11.1.1 Autoimmune conditions that target epithelium

11.1.1.1 Pemphigus vulgaris

Pemphigus vulgaris (PV) is a rare autoimmune vesiculobullous condition that causes mucosal and cutaneous lesions, with oral involvement often being the first sign of the disease. If left untreated, PV can be life-threatening due to extensive skin ulcerations and infection. The skin lesions appear as blistering eruptions (vesicles or bullae) with a raw erythematous base. Any mucosal and/or skin surface can be involved, including oral as well as conjunctival, pharyngeal, and laryngeal mucosa. Oral vesicles and bullae are rarely observed as they quickly break down, resulting in large, irregular ulcerations (Figure 11.1). During clinical examination of patients with autoimmune vesiculobullous disorders, a blister can be induced secondary to soft tissue manipulation, which is referred to as a positive Nikolsky sign.

Pemphigus is characterized by the production of autoantibodies to desmogleins (integral proteins in the desmosomes that confer epithelial cell to cell adhesion), which can be detected in affected tissues (via direct immunofluorescence [DIF]; see chapter 1) as well as in the systemic circulation (via serum-based indirect immunofluorescence [IIF] or enzyme-linked immunosorbent assay [ELISA]). Intact biopsy specimens of pemphigus may reveal ­intraepithelial separation with preservation of the epithelial basal cell layer, often described as a “row of tombstones.” Diagnosis should be confirmed by DIF, which reveals autoantibodies (usually IgG or IgM and complement) in the intercellular spaces between the epithelial cells, resulting in the classic “fishnet” appearance (Figure 11.2). IIF evaluates circulating blood for the presence of specific immunoreactants directed against epithelial structures and may be useful in distinguishing pemphigus from pemphigoid and other oral diseases. In PV, IIF antibody titers correlate to the level of clinical disease and can be useful in assessing response to therapy. Further, autoantibody tests for levels of PV antigens desmogleins 1 and 3 are commercially available and correlate to disease activity in a similar manner as IIF findings.

Paraneoplasic pemphigus is a PV-like disease that occurs infrequently in patients with an underlying neoplasm and/or lymphoproliferative disorder, with the most frequent being non-Hodgkin lymphoma, Castleman disease, chronic lymphocytic leukemia, thymoma, sarcoma, and lung carcinoma. This disorder tends to have a severe and progressive phenotype, with extensive and painful ulcerations primarily affecting the lips, tongue, soft palate, and conjunctiva. Certain drugs like captopril and penicillamine can trigger a PV-like drug hypersensitivity reaction that reverses once the drug is withdrawn.

11.1.1.2 Pemphigoid

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, is a vesiculobullous autoimmune disease that affects oral and other mucosal surfaces including conjunctival, nasal, and vaginal mucosa. Skin lesions associated with pemphigoid are characterized by bullae that eventually rupture, followed by crusting and healing without scarring. A significant complication of MMP with ocular involvement is conjunctival scarring (symblepharon) and blindness; therefore all patients diagnosed with pemphigoid require monitoring by an ophthalmologist. Pemphigoid is characterized by autoantibodies directed against hemidesmosomes, which connect the basal ­epithelium to the basement membrane and the underlying connective tissue, resulting in subepithelial separation and bulla formation. Intact intraoral blisters are observed more frequently compared with PV due to the greater thickness of the blister “roof” (Figure 11.3). Eventually bullae rupture, producing ulcerated lesions that appear ­clinically similar to those of PV and generally heal without scarring. MMP often presents as a desquamative gingivitis, in which the gingival epithelium spontaneously sloughs or can be easily removed with minor manipulation, resulting in erythematous and/or ­ulcerated gingiva.

Biopsy specimens of pemphigoid demonstrate a split between the epithelium and the underlying connective tissue, with complete separation of the basal epithelium from the basement membrane. DIF shows a continuous linear band of immunoreactants (usually IgG and C3) directed at the basement membrane zone (Figure 11.4). IIF for pemphigoid is of limited diagnostic value since circulating antibodies in serum are not consistently present and titers do not correlate with disease activity.

11.1.2 Autoimmune conditions that target connective tissue

11.1.2.1 Lupus erythematosus

Lupus erythematosus (LE) is the most common autoimmune connective tissue disorder and has a wide spectrum of disease presentation mediated by the deposition of immune complexes into various organs. Systemic lupus erythematosus (SLE) is a multisystem disease characterized by a cutaneous rash of the malar region secondary to sun exposure (with a “butterfly” appearance; Figure 11.5), renal dysfunction, musculoskeletal manifestations (arthritis and myalgias), cardiac complications (vasculitis, pericarditis, or non-bacterial endocarditis with vegetations affecting the heart valves, termed Libman-Sacks ­endocarditis), and thrombocytopenia (Table 11.1). Oral involvement develops in up to 25% of patients and may present as areas of lichenoid inflammation (section 11.2.2) or non-specific ulcerations that clinically resemble other common oral ulcerative conditions (i.e., recurrent aphthous ulcerations; Table 11.2).

Table 11.1 American College of Rheumatology criteria for classification of systemic lupus erythematosus.^*

*Modified from http://www.rheumatology.org/practice/clinical/classification/SLE/1997_update_of_the_1982_acr_revised_criteria_for_classification_of_sle.pdf, accessed February 28, 2012.

Chronic cutaneous lupus erythematosus (CCLE) or discoid lupus is a variant of LE in which lesions are generally limited to skin and mucosal surfaces with few or no systemic signs. Skin lesions are characterized by scaly, erythematous patches that typically present on sun-exposed skin surfaces, and healing may result in scarring and hypo- or ­hyperpigmentation. Oral manifestations of CCLE include classic lichenoid lesions, with characteristic erosions surrounded by white, radiating striae (Figure 11.6).

Table 11.2 Clinical and laboratory findings of autoimmune, immune-mediated, and allergic conditions with oral manifestations.

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