AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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. Those diseases in which oral involvement occurs include pemphigus vulgaris (dogs, cats), paraneoplastic pemphigus (1 dog), bullous pemphigoid (dogs, cats, horses), mucous membrane pemphigoid (dogs, cats), 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. 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.

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.
• 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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.
  • 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.
• 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.

• 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. 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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Hyperplastic candidiasis
Herpes simplex infection

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Direct immunofluorescence microscopy
• • Direct immunofluorescence microscopy (DIF) determines the types and locations of immune deposits within patients' epithelial tissues.
  • DIF detects deposits at the epithelial cell surfaces and at the epithelial basement membrane zone of the perilesional skin biopsy specimens obtained from patients with the diseases of the pemphigus and pemphigoid groups, respectively.
  • In paraneoplastic pemphigus, DIF usually reveals deposits at both the epithelial cell surfaces and the epithelial basement membrane zone.
• Indirect immunofluorescence microscopy
• • Indirect immunofluorescence microscopy (IIF) determines the patterns of patients' circulating autoantibodies that bind the epithelial components.
  • IIF detects epithelial cell surface-binding and epithelial basement membrane zone-binding autoantibodies in patients with diseases of the pemphigus and pemphigoid groups, respectively. The titer of the circulating autoantibodies corresponds to the severity of disease in pemphigus.
  • In addition to binding to squamous epithelial cell surfaces (eg, skin, esophagus substrates), circulating autoantibodies from patients with paraneoplastic pemphigus also label transitional epithelium (eg, lumen of rat bladder).
• Indirect immunofluorescence on salt-split substrate
• • Indirect immunofluorescence on salt-split substrate (ssIIF) uses epithelial substrates in which the lamina lucida of the basement membrane zone has been split at the middle, leaving the target antigens for the autoantibodies of bullous pemphigoid and epidermolysis bullosa acquisita to the roof and the base of the split substrate, respectively.
  • Using salt-split epithelial substrates, ssIIF detects the circulating autoantibodies from patients with bullous pemphigoid and epidermolysis bullosa acquisita binding respectively to the roof and the base of the substrates, thus distinguishing these 2 diseases.
  • In patients with mucous membrane pemphigoid, their circulating autoantibodies can bind to the roof, the base, or both, corresponding to the heterogeneity of the target antigens recognized by these autoantibodies.

Imaging Studies

• No imaging studies generally are needed for establishing diagnoses for patients with oral manifestations of autoimmune blistering diseases; however, in patients with paraneoplastic pemphigus, a vigorous search for internal malignancies should be performed. Whenever patients' symptoms are suggestive, perform imaging studies (eg, CT scan, x-ray, bone scan, MRI, ultrasound).
• Order dental periapical x-rays in patients with autoimmune blistering disease affecting the gingival mucosa to rule out periodontal disease.

Other Tests

• Immunoelectron microscopy
• • Two methods of immunoelectron microscopy (IEM) can be used to delineate the ultrastructural location of the target antigens, direct method of IEM (DIEM) and indirect method of IEM (IIEM). Whereas DIEM uses patients' epithelial tissues, IIEM uses patients' circulating autoantibodies (serum study). IEM tests are used primarily to study the various autoantigens in the epithelial basement membrane zone.
  • IEM detects the target antigens (BP180) for bullous pemphigoid, linear IgA bullous dermatosis, and a certain subset of mucous membrane pemphigoid at the upper lamina lucida/hemidesmosome areas; detects the target antigens laminin-5 and laminin-6 for a certain subset of mucous membrane pemphigoid at the lower lamina lucida; and detects the target antigen, type VII collagen, for epidermolysis bullosa acquisita at the lamina densa and sublaminar densa areas.
• Immunoblotting
• • Immunoblotting (IB) test delineates the molecular sizes of the target antigens that are immunolabeled by patients' autoantibodies.
  • IB test is able to detect that the autoantibodies from patients with bullous pemphigoid and certain subsets of mucous membrane pemphigoid recognize a 230-kd (BPAg1) and/or a 180-kd (BPAg2) epithelial proteins; that the autoantibodies from patients with certain subset of mucous membrane pemphigoid recognize one or all of the 3 protein subunits, 200-kd/165-kd (alpha chain), 140-kd (beta chain), and 155-kd/105-kd (gamma chain) of laminin-5; and that the autoantibodies from patients with epidermolysis bullosa acquisita recognize the 290-kd type VII collagen.
• Enzyme-linked immunosorbent assay
• • Enzyme-linked immunosorbent assay (ELISA) test detects the target antigens of circulating autoantibodies from patients using the known recombinant proteins.
  • ELISA test detects autoantibodies that recognize their autoantigens in nondenatured form; therefore, it is a more sensitive detection method than IB test. ELISA test also can be a quantitative method.
• Immunoprecipitation
• • Immunoprecipitation (IP) test detects the target antigens of circulating autoantibodies from patients.
  • IP test detects autoantibodies that recognize their autoantigens in native form; therefore, it is a more sensitive detection method than IB test but is more difficult to perform.

Procedures

• No diagnostic procedures for cancer detection above those age-related tests generally are needed for oral manifestations of autoimmune blistering diseases; however, when encountering patients with paraneoplastic pemphigus, a vigorous search for internal malignancies should be performed. Besides a thorough history and physical examination, when patients' symptoms are suggestive, proper use of diagnostic procedures (eg, colonoscopy, upper GI endoscopy) may be needed.

Histologic Findings

Histology determines the levels in which the blisters occur and the types of inflammatory infiltrates, both of which help determine the final diagnosis. Histopathology delineates the blisters occurring within the epithelium and below the epithelium for the diseases of the pemphigus and pemphigoid groups, respectively. In addition to blisters occurring at the epithelium level, histology of paraneoplastic pemphigus reveals a lichenoid pattern of inflammatory cell infiltration and necrotic epithelial cells.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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).
• 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.

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.
• 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

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

Drug Category: Anti-inflammatory agents

Used to treat oral lesions.

Drug Name	Dapsone (Avlosulfon)
Description	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.
Adult Dose	100 mg PO qd or 50 mg PO bid
Pediatric Dose	>10 years: 25-50 mg PO qd or 25-50 mg PO bid; consult pediatrician before prescribing
Contraindications	Documented hypersensitivity; G-6-PD deficiency
Interactions	May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, such as pyrimethamine (monitor for agranulocytosis during the second and third mo of therapy); probenecid increases dapsone toxicity; trimethoprim with dapsone may increase toxicity of both drugs; dapsone levels may significantly decrease when administered concurrently with rifampin due to increased in renal clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform weekly CBC counts (first mo), then perform CBC counts monthly (6 mo), and then semi-annually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is seen; methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation; patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light

Drug Name	Tetracycline (Sumycin)
Description	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.
Adult Dose	500 mg PO qid
Pediatric Dose	<8 years: Not recommended >8 years: 25-50 mg/kg (10-20 mg/lb) PO qid; consult pediatrician before prescribing
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, and bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increasing risk of pregnancy; tetracycline can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Niacinamide (Vitamin B-3)
Description	Source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis.
Adult Dose	500 mg PO qid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active liver disease or unexplained, significant increases in AST and ALT; large doses of niacin, especially when administered in a sustained-release form (associated with severe hepatotoxicity); patients who have a definite and recent history of peptic ulcer disease (can reactivate ulcers)
Interactions	Cutaneous vasodilation may be a problem if high dose used with peripheral dilators (eg, nitroglycerin); taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated adverse effects of niacin (eg, flushing, itching); clonidine may inhibit niacin-induced flushing
Pregnancy	A - Safe in pregnancy
Precautions	Caution in gallbladder disease or diabetes and those predisposed to gout; monitor blood glucose and liver enzymes; may elevate uric acid levels; pregnancy category C when used at doses greater than RDA

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 percent 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.
• Educate patients about the need for calcium and vitamin D supplements while using systemic corticosteroids.
• Educate patients to monitor the signs and symptoms of infection in order to report possible complications to physicians in a timely manner.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to perform appropriate testing (ie, routine histology, immunofluorescence) to secure the correct diagnosis
• Failure to appropriately monitor patients on systemic therapy for development of adverse effects, signs of toxicity, and response to therapy
• Failure to monitor patients' symptom on possible rectal, laryngeal, and esophageal involvement of the disease
• Failure to investigate and detect the possible benign or malignant neoplasms associated with paraneoplastic pemphigus

Special Concerns

• Elderly patients who have other significant health problems (eg, diabetes mellitus, hypertension, heart diseases) may require treatment with a more conservative approach (eg, topical corticosteroids, tetracycline). The goal of treatment is to achieve disease control with low doses of medications and minimal adverse effects.
• For pemphigus vulgaris, the oral lesions are usually first to surface and last to resolve in any given patient.
• For paraneoplastic pemphigus, the intractable hemorrhagic stomatitis is extremely painful and could cause substantial morbidity for patients with this disease.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Oral manifestations, including blisters, hemorrhagic erosions, and crusts, are shown on a patient with pemphigus vulgaris.
	View Full Size Image
Media type:  Photo

Media file 2:  Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.
	View Full Size Image
Media type:  Image

Media file 3:  Oral manifestations of mucous membrane pemphigoid (also known as cicatricial pemphigoid). Inflammatory gingival changes are characteristic of the disease.
	View Full Size Image
Media type:  Photo

Media file 4:  Direct immunofluorescence microscopy performed on biopsy specimen obtained from a patient with mucous membrane pemphigoid detects linear immunoglobulin G deposits at the epithelial basement membrane zone.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Amagai M, Nishikawa T, Nousari HC, et al. Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest. Aug 15 1998;102(4):775-82. [Medline].
• American College of Rheumatology. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. American College of Rheumatology Task Force on Osteoporosis Guidelines. Arthritis Rheum. Nov 1996;39(11):1791-801. [Medline].
• Anhalt GJ. Pemphigoid. Bullous and cicatricial. Dermatol Clin. Oct 1990;8(4):701-16. [Medline].
• Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. Dec 20 1990;323(25):1729-35. [Medline].
• Balding SD, Prost C, Diaz LA, et al. Cicatricial pemphigoid autoantibodies react with multiple sites on the BP180 extracellular domain. J Invest Dermatol. Jan 1996;106(1):141-6. [Medline].
• Bernard P, Prost C, Lecerf V, et al. Studies of cicatricial pemphigoid autoantibodies using direct immunoelectron microscopy and immunoblot analysis. J Invest Dermatol. May 1990;94(5):630-5. [Medline].
• Borradori L, Lombardi T, Samson J, et al. Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD20 (+) follicular lymphoma-associated paraneoplastic pemphigus. Arch Dermatol. 2001;137:269-272. [Medline].
• Busquets AC, Jean-Baptiste S, Chan LS. Primary brain B-cell lymphoma developing in a patient with pemphigus vulgaris receiving immunosuppressive drugs. Br J Dermatol. Sep 2001;145(3):510-2. [Medline].
• Chan LS, Traczyk T, Taylor TB, et al. Linear IgA bullous dermatosis. Characterization of a subset of patients with concurrent IgA and IgG anti-basement membrane autoantibodies. Arch Dermatol. Dec 1995;131(12):1432-7. [Medline].
• Chan LS, Hammerberg C, Cooper KD. Significantly increased occurrence of HLA-DQB1*0301 allele in patients with ocular cicatricial pemphigoid. J Invest Dermatol. Feb 1997;108(2):129-32. [Medline].
• Chan LS, Majmudar AA, Tran HH, et al. Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of cicatricial pemphigoid. J Invest Dermatol. Jun 1997;108(6):848-53. [Medline].
• Chan LS, Vanderlugt CJ, Hashimoto T, et al. Epitope spreading: lessons from autoimmune skin diseases. J Invest Dermatol. Feb 1998;110(2):103-9. [Medline].
• Chan LS, Regezi JA, Cooper KD. Oral manifestations of linear IgA disease. J Am Acad Dermatol. Feb 1990;22(2 Pt 2):362-5. [Medline].
• Chan LS, Hammerberg C, Cooper KD. Cicatricial pemphigoid. Identification of two distinct sets of epidermal antigens by IgA and IgG class circulating autoantibodies. Arch Dermatol. Nov 1990;126(11):1466-8. [Medline].
• Chan LS, Soong HK, Foster CS, et al. Ocular cicatricial pemphigoid occurring as a sequela of Stevens-Johnson syndrome. JAMA. Sep 18 1991;266(11):1543-6. [Medline].
• Chan LS, Yancey KB, Hammerberg C, et al. Immune-mediated subepithelial blistering diseases of mucous membranes. Pure ocular cicatricial pemphigoid is a unique clinical and immunopathological entity distinct from bullous pemphigoid and other subsets identified by antigenic specificity of autoant. Arch Dermatol. Apr 1993;129(4):448-55. [Medline].
• Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. Mar 2002;138(3):370-9. [Medline].
• Chan LS. Mucous membrane pemphigoid. Clin Dermatol. Nov-Dec 2001;19(6):703-11. [Medline].
• Chan LS. Epitope spreading in paraneoplastic pemphigus: autoimmune induction in antibody-mediated blistering skin diseases. Arch Dermatol. May 2000;136(5):663-4. [Medline].
• Chen M, Chan LS, Cai X, et al. Development of an ELISA for rapid detection of anti-type VII collagen autoantibodies in epidermolysis bullosa acquisita. J Invest Dermatol. Jan 1997;108(1):68-72. [Medline].
• Cranney A, Adachi JD. Corticosteroid-induced osteoporosis: a guide to optimum management. Treat Endocrinol. 2002;1(5):271-9. [Medline].
• Delgado JC, Turbay D, Yunis EJ, et al. A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid. Proc Natl Acad Sci U S A. Aug 6 1996;93(16):8569-71. [Medline].
• Domloge-Hultsch N, Gammon WR, Briggaman RA, et al. Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease. J Clin Invest. Oct 1992;90(4):1628-33. [Medline].
• Domloge-Hultsch N, Anhalt GJ, Gammon WR, et al. Antiepiligrin cicatricial pemphigoid. A subepithelial bullous disorder. Arch Dermatol. Dec 1994;130(12):1521-9. [Medline].
• Duong DJ, Moxley RT 3rd, Kellman RM, et al. Thalidomide therapy for cicatricial pemphigoid. J Am Acad Dermatol. Aug 2002;47(2 Suppl):S193-5. [Medline].
• Fine JD, Neises GR, Katz SI. Immunofluorescence and immunoelectron microscopic studies in cicatricial pemphigoid. J Invest Dermatol. Jan 1984;82(1):39-43. [Medline].
• Gammon WR, Briggaman RA, Inman AO, et al. Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescence on 1.0 M sodium chloride-separated skin. J Invest Dermatol. Feb 1984;82(2):139-44. [Medline].
• Gandhi K, Chen M, Aasi S, et al. Autoantibodies to type VII collagen have heterogeneous subclass and light chain compositions and their complement-activating capacities do not correlate with the inflammatory clinical phenotype. J Clin Immunol. Nov 2000;20(6):416-23. [Medline].
• Kirtschig G, Murrell D, Wojnarowska F, Khumalo N. Interventions for mucous membrane pemphigoid/cicatricial pemphigoid and epidermolysis bullosa acquisita: a systematic literature review. Arch Dermatol. Mar 2002;138(3):380-4. [Medline].
• Kong HH, Prose NS, Ware RE, et al. Successful treatment of refractory childhood pemphigus vulgaris with anti-CD20 monoclonal antibody (rituximab). Pediatr Dermatol. 2005;22:461-464. [Medline].
• Labib RS, Anhalt GJ, Patel HP, et al. Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting. J Immunol. Feb 15 1986;136(4):1231-5. [Medline].
• Lazarova Z, Yee C, Darling T, et al. Passive transfer of anti-laminin 5 antibodies induces subepidermal blisters in neonatal mice. J Clin Invest. Oct 1 1996;98(7):1509-18. [Medline].
• Lee MS, Wakefield PE, Konzelman JL Jr, James WD. Oral insertable prosthetic device as an aid in treating oral ulcers. Arch Dermatol. Apr 1991;127(4):479-80. [Medline].
• Leverkus M, Bhol K, Hirako Y, et al. Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and bullous pemphigoid 230. Br J Dermatol. Dec 2001;145(6):998-1004. [Medline].
• Liu Z, Diaz LA, Troy JL, et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest. Nov 1993;92(5):2480-8. [Medline].
• Lozada-Nur F, Miranda C, Maliksi R. Double-blind clinical trial of 0.05% clobetasol propionate (corrected from proprionate) ointment in orabase and 0.05% fluocinonide ointment in orabase in the treatment of patients with oral vesiculoerosive diseases. Oral Surg Oral Med Oral Pathol. Jun 1994;77(6):598-604. [Medline].
• Lozada-Nur F, Huang MZ, Zhou GA. Open preliminary clinical trial of clobetasol propionate ointment in adhesive paste for treatment of chronic oral vesiculoerosive diseases. Oral Surg Oral Med Oral Pathol. Mar 1991;71(3):283-7. [Medline].
• Lozada-Nur F. Predisnoe and azathioprine in the treatment of patients with vesiculoerosive oral diseases. Oral Surg Oral Med Oral Pathol. 1981;52:257-60.
• Luke MC, Darling TN, Hsu R, et al. Mucosal morbidity in patients with epidermolysis bullosa acquisita. Arch Dermatol. Aug 1999;135(8):954-9. [Medline].
• Mobini N, Nagarwalla N, Ahmed AR. Oral pemphigoid. Subset of cicatricial pemphigoid?. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Jan 1998;85(1):37-43. [Medline].
• Nanda A, Dvorak R, Al-Saeed K, et al. Spectrum of autoimmune bullous diseases in Kuwait. Int J Dermatol. 2004;43:876-881. [Medline].
• Nguyen VT, Ndoye A, Bassler KD, et al. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol. Feb 2001;137(2):193-206. [Medline].
• Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. May 6 1999;340(18):1406-10. [Medline].
• Olivry T, Dunston SM, Schachter M, et al. A spontaneous canine model of mucous membrane (cicatricial) pemphigoid, an autoimmune blistering disease affecting mucosae and mucocutaneous junctions. J Autoimmun. Jun 2001;16(4):411-21. [Medline].
• Olivry T, Chan LS. Autoimmune blistering dermatoses in domestic animals. Clin Dermatol. Nov-Dec 2001;19(6):750-60. [Medline].
• Olivry T, Mirsky ML, Singleton W, et al. A spontaneously arising porcine model of bullous pemphigoid. Arch Dermatol Res. Jan 2000;292(1):37-45. [Medline].
• Olivry T, Chan LS, Xu L, et al. Novel feline autoimmune blistering disease resembling bullous pemphigoid in humans: IgG autoantibodies target the NC16A ectodomain of type XVII collagen (BP180/BPAG2). Vet Pathol. Jul 1999;36(4):328-35. [Medline].
• Poskitt L, Wojnarowska F. Treatment of cicatricial pemphigoid with tetracycline and nicotinamide. Clin Exp Dermatol. May 1995;20(3):258-9. [Medline].
• Robinson ND, Hashimoto T, Amagai M, Chan LS. The new pemphigus variants. J Am Acad Dermatol. May 1999;40(5 Pt 1):649-71; quiz 672-3. [Medline].
• Rogers RS 3rd, Sheridan PJ, Nightingale SH. Desquamative gingivitis: clinical, histopathologic, immunopathologic, and therapeutic observations. J Am Acad Dermatol. Dec 1982;7(6):729-35. [Medline].
• Rogers RS 3rd, Seehafer JR, Perry HO. Treatment of cicatricial (benign mucous membrane) pemphigoid with dapsone. J Am Acad Dermatol. Feb 1982;6(2):215-23. [Medline].
• Salopek TG, Logsetty S, Tredget EE, et al. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol. 2002;47:785-788. [Medline].
• Sambrook PN. How to prevent steroid induced osteoporosis. Ann Rheum Dis. Feb 2005;64(2):176-8. [Medline].
• Schmidt E, Benoit S, Brocker EB, et al. Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab. Arch Dermatol. 2006;142:147-150. [Medline].
• Schumann H, Baetge J, Tasanen K, et al. The shed ectodomain of collagen XVII/BP180 is targeted by autoantibodies in different blistering skin diseases. Am J Pathol. Feb 2000;156(2):685-95. [Medline].
• Setterfield J, Shirlaw PJ, Kerr-Muir M, et al. Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA signifies a more severe and persistent disease. Br J Dermatol. Apr 1998;138(4):602-10. [Medline].
• Setterfield J, Shirlaw PJ, Bhogal BS, et al. Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies correlate with disease activity. Br J Dermatol. Apr 1999;140(4):645-50. [Medline].
• Shimizu H, Masunaga T, Ishiko A, et al. Autoantibodies from patients with cicatricial pemphigoid target different sites in epidermal basement membrane. J Invest Dermatol. Mar 1995;104(3):370-3. [Medline].
• Silverman S Jr, Gorsky M, Lozada-Nur F, Liu A. Oral mucous membrane pemphigoid. A study of sixty-five patients. Oral Surg Oral Med Oral Pathol. Mar 1986;61(3):233-7. [Medline].
• Sitaru C, Schmidt E, Petermann S, et al. Autoantibodies to bullous pemphigoid antigen 180 induce dermal-epidermal separation in cryosections of human skin. J Invest Dermatol. Apr 2002;118(4):664-71. [Medline].
• Sitaru C, Mihai S, Otto C, et al. Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen. J Clin Invest. Apr 2005;115(4):870-8. [Medline].
• Thornhill M, Pemberton M, Buchanan J, Theaker E. An open clinical trial of sulphamethoxypyridazine in the treatment of mucous membrane pemphigoid. Br J Dermatol. Jul 2000;143(1):117-26. [Medline].
• Wojnarowska F, Marsden RA, Bhogal B, Black MM. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol. Nov 1988;19(5 Pt 1):792-805. [Medline].
• Xu L, Robinson N, Miller SD, Chan LS. Characterization of BALB/c mice B lymphocyte autoimmune responses to skin basement membrane component type XVII collagen, the target antigen of autoimmune skin disease bullous pemphigoid. Immunol Lett. Jun 1 2001;77(2):105-11. [Medline].
• Zillikens D, Rose PA, Balding SD, et al. Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies. J Invest Dermatol. Oct 1997;109(4):573-9. [Medline].
• van der Waal RI, Pas HH, Nousari HC, et al. Paraneoplastic pemphigus caused by an epithelioid leiomyosarcoma and associated with fatal respiratory failure. Oral Oncol. Jul 2000;36(4):390-3. [Medline].

Article Last Updated: Aug 30, 2006