eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Oral Manifestations of Autoimmune Blistering Diseases

Author: Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine
Coauthor(s): Thierry Olivry, PhD, DrVet, Associate Professor of Dermatology, Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine; Francina Lozada-Nur, DDS, MS, MPH, Professor Emeritis of Clinical Oral Medicine, Step VII, Department of Orofacial Sciences, Division of Oral Medicine, Oral Pathology and Oral Radiology, School of Dentistry, Former Director of Advance Program Oral Medicine, University of California at San Francisco School of Dentistry
Contributor Information and Disclosures

Updated: Oct 23, 2008

Introduction

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.

Clinical

History

Autoimmune blistering skin diseases generally have an insidious onset.

  • When oral lesions are present, they invariably are symptomatic, varying from mild to unbearable pain.
  • Patients with mucous membrane pemphigoid often complain of spontaneous gum bleeding.
  • Lesions start to surface in the oral cavity by approximately 6 months prior to the skin lesions in most patients with pemphigus vulgaris.
  • In some patients who have oral manifestations of autoimmune blistering diseases, the symptoms are so severe that they prevent them from proper dietary intake, resulting in severe malnutrition.
  • In patients who have rectal involvement, pain and bleeding could be early symptoms.
  • In patients with laryngeal involvement, hoarseness could be an early symptom.
  • Intractable hemorrhagic stomatitis is highly suggestive of paraneoplastic pemphigus.

Physical

Oral manifestations of autoimmune blistering diseases generally can affect any area of the oral cavity, including the gingiva, palate, buccal, tongue, floor of the mouth, and pharynx. In the pemphigus disease group, the blisters are broken easily; therefore, they rarely are observed clinically. Instead, erosions and superficial ulcers more likely are observed. In the pemphigoid disease group, because the blisters are situated deeply, they are more likely to be observed intact clinically.

  • Pemphigus vulgaris
    • Oral lesions occur in most patients with pemphigus vulgaris.
    • In most patients, the oral mucous membranes are affected within 6 months of disease onset. In some patients, it remains exclusively an oral disease for months or years before generalized skin disease develops.
    • Typically, small blisters rapidly evolve into erosions covered with white-yellow pseudomembranes.
    • All areas of oral mucous membranes, gingiva, buccal, palate, tongue, and floor of the mouth can be affected.
    • A subgroup of patients with pemphigus vulgaris does not develop skin disease.
  • Pemphigus foliaceus is predominantly a skin disease. Oral or other mucous membrane involvements are very rare. In skin, desmoglein-3 is present predominantly in the lower layers of epithelial cells. By contrast, the layers of desmoglein-3 are present throughout the upper and lower layers of epithelium in the oral mucous membrane. Thus, the autoantibodies of patients with pemphigus foliaceus, which exclusively target desmoglein-1, are unable to break down the adherence of the upper layers of epithelium of oral mucosa, which is protected by the presence of desmoglein-3.
  • Paraneoplastic pemphigus
    • Oral lesions, which are invariably present in this disease, can precede, follow, or appear at the same time of neoplasm discovery.8
    • Severe mucositis with hemorrhagic blisters, erosion, or ulceration can be observed in various oral mucosae.
    • Lesions at the vermilion border almost always are present.
  • In patients with bullous pemphigoid, oral lesions rarely are observed. If present, they usually are mild and consist of small blisters or erosions.
  • In the rare occurrence of lichen planus pemphigoides, small blisters and flat, linear, white, netlike striae that characterize lichen planus can occur in oral mucous membranes.
  • With linear IgA bullous dermatosis (of adult and children), the oral lesions, rarely present, are similar to that of bullous pemphigoid or can mimic aphthaelike ulcers.9
  • Oral lesions in epidermolysis bullosa acquisita commonly are observed. The lesions are deep-seated blisters, erosions, and ulcers, sometimes hemorrhagic. Milia are clinically observed.
  • Mucous membrane pemphigoid
    • The oral mucous membrane is the most frequently affected site in this heterogeneous group of diseases, followed by ocular, skin, nasal, genital, pharyngeal, esophageal, laryngeal, and anal mucous membranes.
    • Approximately 50% of patients with mucous membrane pemphigoid have oral mucosal lesions.

Causes

Autoimmune blistering diseases generally are caused by autoantibodies targeting the skin components of the epithelial cell surfaces or basement membrane zone. Certain human leukocyte antigen (HLA) alleles have been reported to be associated with autoimmune blistering diseases. For example, HLA-DQB1*0301 is associated strongly with bullous pemphigoid and mucous membrane pemphigoid.10,11

  • Pemphigus group
    • Desmoglein-3 is the primary target antigen in pemphigus vulgaris, whereas desmoglein-1 is the exclusive target antigen in pemphigus foliaceus.
    • In passive transfer experiments, these autoantibodies apparently induced (in newborn mice) blisters that have similar histology as the human diseases. These autoantibodies apparently are capable of inducing the blisters without the help of complement components; however, autoantibodies against desmoglein-1 are present in patients with pemphigus vulgaris and are capable of inducing blisters in newborn mice.
  • Paraneoplastic pemphigus
    • The true cause of paraneoplastic pemphigus is not yet firmly established.
    • Some patients have autoantibodies against desmoglein-3, and these autoantibodies can induce blisters in newborn mice.12 The possible link between the underlying neoplasm and autoimmunity may be due to an immune dysregulation secondary to the presence of neoplasm. In addition to autoantibodies to desmoglein-3, most patients developed autoantibodies to many intracellular epithelial components, desmoplakins I and II, periplakin, envoplakin, BP230 (BPAg1), and a 170-kd membrane protein. Several other smaller proteins recently have been found to be involved. Autoantibodies to these intracellular components probably are developed as a secondary autoimmune response rather than a primary cause.
    • The association of neoplasms with paraneoplastic pemphigus is clearly established. The most common associated benign tumor is thymoma, followed by Castleman tumor, a rare and complex lymphoproliferative disease. The most common associated malignant tumor is non-Hodgkin lymphoma, followed by chronic lymphocytic leukemia.
  • Pemphigoid group
    • Autoantibodies to BP180 are the likely inducing autoantigen.
    • Passive transfer experiments using rabbit antimouse BP180 antibodies induce blisters in newborn mice, and the blister induction apparently is complement dependent.
    • The target antigen for linear IgA bullous dermatosis (childhood and adult) is a truncated BP180 protein.
    • The target antigen for epidermolysis bullosa acquisita is type VII collagen, particularly the noncollagenous (NC1) domain.
  • Mucous membrane pemphigoid
    • In this heterogeneous group of diseases, multiple target antigens have been identified, including BP180, laminin-5, laminin-6, type VII collagen, and beta-4 integrin, but no clinical hallmark distinguishes subsets of patients with regard to the target antigen.
    • Rabbit antibodies generated against laminin-5 can induce blisters in newborn mice.
    • Presently, the link between the autoantibodies and the scarring process that characterizes this group of diseases is missing.

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References
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Further Reading

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Keywords

oral autoimmune blistering diseases, autoimmune diseases, oral lesions, pemphigus vulgaris, bullous pemphigoid, linear immunoglobulin A bullous dermatosis, linear IgA bullous dermatosis, paraneoplastic pemphigus, cicatricial pemphigoid, mucous membrane pemphigoid

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Contributor Information and Disclosures

Author

Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine
Lawrence Chan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois State Medical Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Thierry Olivry, PhD, DrVet, Associate Professor of Dermatology, Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine
Thierry Olivry, PhD, DrVet is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Francina Lozada-Nur, DDS, MS, MPH, Professor Emeritis of Clinical Oral Medicine, Step VII, Department of Orofacial Sciences, Division of Oral Medicine, Oral Pathology and Oral Radiology, School of Dentistry, Former Director of Advance Program Oral Medicine, University of California at San Francisco School of Dentistry
Francina Lozada-Nur, DDS, MS, MPH is a member of the following medical societies: American Academy of Oral Medicine
Disclosure: Nothing to disclose.

Medical Editor

Richard K Scher, MD, Professor of Dermatology, University of North Carolina
Richard K Scher, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Cryosurgery, American College of Physicians, American Dermatological Association, American Geriatrics Society, American Medical Association, Association of Military Surgeons of the US, International Society for Dermatologic Surgery, New York Academy of Sciences, Noah Worcester Dermatological Society, Rhode Island Medical Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Drore Eisen, MD, DDS, Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati
Drore Eisen, MD, DDS is a member of the following medical societies: American Academy of Dermatology, American Academy of Oral Medicine, and American Dental Association
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Disclosure: elsevier Royalty Other; american college of physicians Honoraria Other

 
 
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