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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. 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.

History
Autoimmune blistering skin diseases generally have an insidious onset. The following may be noted on history:

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. Note the following:

In pemphigus vulgaris, oral lesions occur in most patients. 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 (see the image below). A subgroup of patients with pemphigus vulgaris does not develop skin disease.
Oral manifestations, including blisters, hemorrhagic erosions, and crusts, are shown on a patient with pemphigus vulgaris.
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.
In paraneoplastic pemphigus, oral lesions, which are invariably present in this disease, can precede, follow, or appear at the same time of neoplasm discovery. 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 one patient with bullous pemphigoid and hemophilia, extensive bullous lesions occurred in the mouth, along with substantial bleeding.
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.
Oral lesions in epidermolysis bullosa acquisita commonly are observed. The lesions are deep-seated blisters, erosions, and ulcers, sometimes hemorrhagic. Milia are clinically observed.
Regarding 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, as shown in the image below.

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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.

Pemphigus group
Desmoglein-3 is the primary target antigen in pemphigus vulgaris, and 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
No true cause has been firmly established. Some patients have autoantibodies against desmoglein-3, and these autoantibodies can induce blisters in newborn mice. 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 develop autoantibodies to many intracellular epithelial components, desmoplakins I and II, periplakin, envoplakin, BP230 (BPAg1), and a 170-kd membrane protein. Several other smaller proteins are involved.

Autoantibodies to these intracellular components probably develop as a secondary autoimmune response rather than a primary cause. Neoplasms are clearly associated with paraneoplastic pemphigus. 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
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.

Differentials

Aphthous Stomatitis
Behcet Disease
Erythema Multiforme
Herpes Simplex
Herpes Zoster
Lichen Planus
Oral Lichen Planus
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Medical Care
Patients with oral manifestations of autoimmune blistering diseases can be treated conjointly with an oral medicine specialist. Furthermore, patients should have an oral prophylaxis performed by a dental hygienist or dentist prior to initiation of systemic or topical therapy. During the course of therapy, patients should have oral prophylaxis (oral hygiene) performed every 3-4 months. Additionally, they should be monitored for oral candidiasis, especially once on immunosuppressive therapy.

For patients who are treated with systemic corticosteroid, daily calcium and vitamin D supplements are needed to reduce steroid-induced osteoporosis.

For patients who are treated with systemic corticosteroids, steroid-induced osteoporosis should be prevented or reduced by taking an osteoclast-mediated bone resorption inhibitor-bisphosphonate (eg, Fosamax).[18, 19]

For patients who have not responded to more conventional therapies, intravenous infusion of humanized monoclonal antibodies to B cells (anti-CD20, rituximab) could be used, after the precaution to assess for serious infections is taken into account.[20, 21, 22, 23]

Surgical Care
Surgical care usually is not needed in treating the oral manifestations of patients with autoimmune blistering diseases.

Consultations
Examination by pulmonary specialists is recommended for patients with severe oral lesions, especially those patients with paraneoplastic pemphigus if the patients have symptoms or signs suggestive of respiratory difficulty. Respiratory failure and death have been reported in these patients.[24, 25]

Examination by gastroenterologists is recommended for some patients with severe oral lesions to detect possible involvement of the esophagus. Dysphagia can be an associated symptom.

Examination by ophthalmologists experienced in external eye diseases is recommended for those patients with oral lesions and symptoms or signs of ocular inflammation.

Thorough examination by consulting physicians experienced in mucous membrane pemphigoid (cicatricial pemphigoid) is recommended for some patients with oral lesions that also can have genital mucosal involvement.

Care provided by oral medicine specialists or physicians experienced in the field of oral medicine is recommended for patients with severe oral disease.

Diet
Advise patients with oral mucosal manifestations of autoimmune blistering diseases to eat a balanced diet and to avoid rough or spicy foods. Patients generally have no dietary restrictions once the disease is under control.

During periods of flare-up, soft and bland diets are preferred since it will cause less trauma to the injured tissue. Foods with strong acidity and spicy foods should be avoided. Patients with epidermolysis bullosa acquisita should avoid foods with a hard-to-chew quality since this disease tends to be exacerbated by minor trauma.

Activity
Generally, no activity restrictions are recommended for patients with oral manifestations of autoimmune blistering diseases; however, strenuous physical activities may not be advisable for patients with epidermolysis bullosa acquisita since this disease is exacerbated by trauma.

Medication Summary
The treatment strategy for oral manifestations of autoimmune blistering diseases generally is the same as the treatment for the autoimmune blistering diseases themselves; therefore, please see Pemphigus Vulgaris, Bullous Pemphigoid, and Linear IgA Dermatosis for treatment options for those patients with these diseases who have oral involvement.

For cicatricial pemphigoid (mucous membrane pemphigoid) in which mucous membranes primarily are affected, the treatment strategy is discussed in detail in a separate article; therefore, the treatment for mucous membrane pemphigoid is not discussed herein. Adjunct treatments particularly relevant to oral lesions as a result of these autoimmune diseases are outlined below.

Anti-inflammatory agents
Class Summary
Used to treat oral lesions.

Clobetasol (Temovate)

Suppresses mitosis and increases synthesis of proteins that decrease inflammation and cause vasoconstriction. Class I superpotent topical steroid useful in treating oral lesions. Topical corticosteroids commonly are used intraorally for oral manifestations of autoimmune blistering skin diseases. Since these diseases are chronic inflammatory in nature, topical corticosteroids are very useful as an adjunct treatment. Patients with disease confined to the gingiva should see a dentist to have a custom-made soft tray to carry the medication.

Dapsone (Avlosulfon)

Mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Anti-inflammatory mechanism of action remains unknown but probably relates to suppression of neutrophil function. Used alone or in conjunction with other anti-inflammatory medications or immunosuppressives for oral lesions.

Tetracycline (Sumycin)

Mechanism of action probably is by its anti-inflammatory properties, although it is an antibiotic by nature. Can be used alone or in conjunction with niacinamide.

Niacin (Vitamin B-3)

Source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis.

Further Inpatient Care
Inpatient care frequently is required for patients with the pemphigus group of diseases, particularly for those with pemphigus vulgaris and paraneoplastic pemphigus.

Further Outpatient Care
Regular follow-up care for patients with oral and skin manifestations of autoimmune blistering diseases by their dermatologists is recommended when the disease is active and during the tapering of medication when the disease is in remission.

Patients with oral autoimmune blistering disease alone should receive follow-up care from an oral medicine specialist for oral care treatment, otherwise poor oral hygiene will interfere with treatment outcome. Furthermore, complications from poor oral care could lead to periodontal disease and early teeth loss.

During the active disease stage, patient follow-up care every 4-6 weeks is recommended. Patients should be monitored for oral yeast infection. During the clinical remission stage, patient follow-up care every 6 months is recommended.

Transfer
Transferring patients with extremely severe disease with most of the skin denuded to a burn unit for close skin care may be indicated.

Deterrence/Prevention
Institute a combined supplement of calcium and vitamin D for patients treated with systemic corticosteroid for longer than 1 month to prevent osteoporosis. The guideline for dosage and frequency of this supplement is stated in the 1996 recommendations established by the American College of Rheumatology Task Force.

Institute a combined regimen of a non-alcohol–based mouthwash (Biotene mouthwash) and a weekly dose of systemic antifungal medication for patients at risk for oral candidiasis.

Complications
Monitoring treatment complications (eg, infection, osteoporosis, adrenal suppression) for patients receiving long-term immunosuppressive treatments is needed. If observed, treat complications properly.

Prognosis
The prognosis for patients with autoimmune blistering diseases generally is quite good. A small percentage of patients with pemphigus vulgaris do not respond well to treatment, which can lead to a fatal outcome. The prognosis for patients with paraneoplastic pemphigus is poor unless the associated primary neoplasm is found and eradicated.

Patient Education
Educate patients with autoimmune diseases about the nature of the disease and the possible adverse effects of long-term use of immunosuppressives. Also educate patients about the need for calcium and vitamin D supplements while using systemic corticosteroids. Finally, educate patients to monitor the signs and symptoms of infection in order to report possible complications to physicians in a timely manner.