By McCuin, Jill B; Hanlon, Terri; Mutasim, Diya F
Autoimmune bullous diseases are a heterogenous group of diseases characterizfd by cutaneous and mucosal vesicles and bullae. Diagnosis is based on a combination of clinical, histopathological, and immunofluorescence findings. Current treatment, including vigilant wound care, significantly reduces disease morbidity and mortality.
Objectives
This educational activity is designed for nurses and other health care providers who care for and educate patients regarding autoimmune bullous diseases. For those wishing to obtain CE credit, an evaluation follows. After studying the information presented in this article, the nurse will be able to:
1. Describe the characteristics of bullous pemphigoid, mucous membrane pemphigoid, pemphigus vulgaris, and pemphigus foliaceus.
2. Define paraneoplastic pemphigus, epidermolysis bullosa acquisita, and linear IgA dermatosis.
3. List diagnostic and management principles associated with autoimmune bullous diseases.
Bullous diseases are a group of skin disorders in which the primary lesion is a vesicle (1 cm). The main etiologic groups of bullous diseases are autoimmune, allergic, mechanical (inherited), metabolic, and infectious (see Table 1).
The autoimmune bullous diseases are characterized by the production of antibodies to adhesion molecules (Burgeson & Christiano, 1998). In the pemphigoid group of diseases the target adhesion molecules are part of the hemidesmosornes at the dermal- epidermal junction. The pemphigus group is characterized by antibodies against molecules in the desmosomes, between neighboring epithelial cells. Although the targets for the autoantibodies have been characterized, the mechanism of initiation of the autoimmune response is unknown (Diaz & Giudice, 2000). There is no method for preventing this group of diseases, and there is no clearly identified genetic tendency. With current treatment modalities, mortality is low and is more often related to complications of therapy rather than the primary disease. Morbidity can be severe.
Table 1.
Main Etiologic Groups of Bullous Diseases
Figure 1.
Bullous pemphigoid: Note edematous plaques and bullae.
Figure 2.
Bullous pemphigoid: Note edematous plaques and vesicles.
Diseases
Bullous pemphigoid. Bullous pemphigoid (BP) primarily affects individuals greater than 60 years of age. There is no gender or racial predilection. The initial manifestation of the disease ranges from pruritus without clinical lesions to pruritic urticarial papules and plaques. The classic BP lesions are tense bullae, filled with clear fluid, on an erythematous base. These lesions are often generalized, and most commonly involve the lower abdomen, inner thighs, groin, axillae, neck, and flexural aspects of arms and legs (see Figures 1 & 2) (Freedberg et al., 2003).
Ruptured bullae lead to erosions that heal without scarring. These erosions can be an entry for bacterial superinfection. Mucosal lesions can occur, although they are usually mild and transient. The typical course of BP is 5 years. Exacerbations following remission are rare and are mild when they do occur.
Mucous membrane pemphigoid. Mucous membrane pemphigoid (MMP) affects middle-aged to elderly individuals, with a slight female predominance. Approximate incidence is 1 case per 1 million people each year, and there is no racial predilection. MMP can involve any mucous membrane with stratified squamous epithelium. It has a high incidence of oral and ocular involvement (see Figure 3). Other mucous membranes that may be involved are the pharynx, nose, larynx, genitals, rectum, and esophagus. Skin involvement occurs in 10% to 43% of patients (Mutasim, Pelc, & Anhalt, 1993a).
Figure 3.
Mucous membrane pemphigoid: Note bullae and erosion on buccal mucosa.
Oral involvement may occur in the gingiva, buccal mucosa, palate, alveolar ridge, tongue, and lower lip, and is commonly characterized by desquamative gingivitis. The findings include gingival erythema and edema followed by desquamation of gingival mucosa or frank blister formation, resulting in erosions. Another presentation is that of delicate, white, reticulated patches, resembling those seen in lichen planus (Mutasim et al., 1993a).
Ocular involvement presents as chronic intractable conjunctival inflammation that may be unilateral or bilateral. Patients typically complain of a burning sensation, dryness, or foreign-body sensation. As the disease progresses, entropion (inversion of the eyelid margins) and trichiasis (inversion of lashes to the corneal surface) can cause further corneal injury resulting in erosions and neovascularization with eventual blindness. Symblepharon (fusion of the bulbar and palpebral conjunctiva) often occurs as a result of the scarring.
Nasopharyngeal involvement includes erosions of the nasal mucosa, crusting discharge, and epistaxis. It is often painful, and erosions can progress to stenosis and nasal obstruction. Esophageal involvement, which is more difficult to detect, is characterized by heartburn, dysphagia, and phagodynia. A barium swallow and endoscopy, with histologie and immunofluorescence studies, confirm this diagnosis. Laryngeal and tracheal involvement is rare but may be life threatening secondary to sloughing of the mucosa and aspiration. The anorectal area presents as pain on defecation, intermittent bleeding, and narrowing of the anal canal. Pain upon urination or with intercourse is associated with genitourinary involvement. Without treatment MMP has a high morbidity.
Pemphigus vulgaru. Pemphigus vulgaris (PV) is a relatively rare disorder that affects individuals in the 3rd to 5th decades of life (Korman, 1988). Although no genetic pattern has been established, the disease is much more common in persons of Mediterranean and Jewish descent than in the general population (Freedberg et al., 2003). It presents as oral blisters that rupture rapidly and progress to painful erosions. Involvement of other mucous membranes is rare. Most patients develop cutaneous flaccid blisters that rupture easily and leave painful erosions, which are slow to heal (see Figures 4 & 5). These erosions are prone to secondary bacterial infection. Without treatment the disease is progressive and mortality approaches 100%.
Pemphigus foliaceus. Pemphigus foliaceus (PF) typically affects individuals over 50 years of age and is characterized by superficial blisters that rupture and leave shallow erosions that heal without scarring (see Figure 6). Lesions favor the head and upper trunk and almost never present in the mucosal surfaces. Many patients follow a chronic course with this disease, but have a lower morbidity than those with PV due to the superficial nature of the erosions and the lack of mucosal involvement (Mutasim, Pelc, & Anhalt, 1993b).
Paraneoplastic pemphigus. Paraneoplastic pemphigus (PNP) is associated with malignant and benign neoplasms. Mucous membrane involvement is a prominent feature. Patients typically present with persistent, painful blisters or erosions of lips, gingival, buccal, and lingual mucosa. Other areas where erosions can present include nasopharynx, oropharynx, nasal septum, epiglottis, hypopharynx, tracheobronchial mucosa, esophagus, and the ocular and genital areas.
The cutaneous lesions are polymorphous and pruritic, and can mimic erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, morbilliform drug eruption, lichen planus, BP, or lichen planus pemphigoides. The most commonly associated neoplasms are non- Hodgkin’s lymphoma, chronic lymphocytic lymphoma, or Castleman’s disease (giant lymph node hyperplasia). Diagnosis of the neoplasm typically precedes or shortly follows the development of PNP (Anhalt et al., 1990).
Figure 4.
Pemphigus vulgaris: Note erosions and flaccid bullae.
Figure 5.
Pemphigus vulgaris: Note oral erosions.
Epidermolysis bullosa acquisita. Epidermolysis bullosa acquisita (EBA) affects middle age to elderly individuals with no gender or racial predilection. There are multiple types of EBA. The classical presentation is spontaneous or traumainduced blisters on the dorsum of hands, elbows, knees, or other trauma-prone sites. Chronic lesions are associated with scarring and milia formation. EBA may also be primarily or exclusively mucosal, and clinically indistinguishable from MMP. Finally, EBA can present as generalized blisters with underlying inflammation similar to BP (Gammon, Briggaman, Woodley, Heald, & Wheeler, 1984).
Linear IgA dermatosis. Linear IgA dermatosis (LAD) is a symmetrical, generalized bullous eruption that is often pruritic (see Figure 7). Mucosal involvement is common. It can be mild and asymptomatic, or can be significant and scarring, similar to that in MMP. LAD has been reported in association with multiple drugs including vancomycin, lithium, furosemide, atorvastatin, captopril, and diclofenac (Freedberg et al., 2003). Therefore, a thorough medication history should be elicited from patients.
Diagnosis
In addition to history and physical examination, the diagnosis of bullous diseases is based on histopathology and immunofluorescence (Mutasim & Diaz, 1991). The specimen for histopathological examination should be a shave biopsy of an early, small, intact vesicle. This type of specimen is most likely to reveal the primary pathology, including the location of the split (intraepidermal or subepidermal) without secondary changes such as infection, in\flammation, or ulceration. It may also help differentiate this group of diseases from others that can present clinically with vesicles or bullae (see Table 1).
Direct immunofluorescence (DIF) highlights the location of the autoantibodies in the epidermis or basement membrane zone. A biopsy specimen from normal-appearing skin immediately adjacent to a clinical lesion (perilesional skin) is incubated with fluorescently tagged antibody probes (Mutasim, Pelc, & Supapannachart, 1993). The pattern of binding is often diagnostic and correlates with the location of the target antigen. The ideal specimen is either a shave or a punch biopsy of perilesional skin, which is normal-appearing skin adjacent to a clinical lesion. The inflammation and vesicle- formation in lesional skin can obscure the diagnostic patterns of antibody binding.
Indirect immunofluorescence (IIF) reveals the binding location and pattern of circulating autoantibodies (Beutner, Chorzelski, & Kumar, 1987). The sample for IIF is blood, serum, or blister fluid. This is incubated with standard epithelial substrates and the pattern of antibody binding is visualized with a fluorescent microscope. As in DIF, the pattern of binding is often diagnostic and correlates with the location of the target antigen.
Pathophysiology
Bullous diseases are caused by an autoimmune response to the adhesion molecules either in the desmosomes between epithelial cells, or in the basement membrane zone between the basal layer and the underlying dermis. After binding to their target antigens the antibodies cause blister formation in one of two ways: (a) direct disruption of intercellular adhesion interactions or (b) initiation of inflammation leading to destruction of adhesion molecules. The first mechanism underlies the pemphigus group (Amagai, Karpati, Prussick, & Klaus-Kovtun, 1992) of diseases and the second the pemphigoid group (Liu et al., 1997).
Figure 6.
Pemphigus foliaceus: Note shallow erosions on back.
Figure 7.
Linear IgA dermatosis: Note erythema and bullae.
Table 2.
Drugs for the Three Main Areas of Therapy
Management
Before treatment is initiated, an accurate diagnosis should be made by combining the clinical, histopathological, and immunofluorescence findings. The three main goals of therapy are suppression of the immune response (antibody production), inhibition of inflammation (see Table 2), and wound care.
Choice of a specific agent is guided by disease-related and patient-related factors. Diseaserelated considerations include the type of disease as well as severity. For example, the pemphigus group of diseases is mediated by direct disruption of intercellular adhesion interactions so suppression of antibody production is needed. In the pemphigoid group, however, inflammation leads to vesicle formation so anti-inflammatory agents are employed. Patient- related factors include age, co-morbidities, compliance, etc. Duration of treatment is often prolonged (months to years) depending on the patient’s disease and response to therapy.
Corticosteroids are often the first agent used. Although mild to moderate disease may be treated with topical Corticosteroids, systemic therapy is required for more extensive disease activity. Corticosteroids are both anti-inflammatory as well as immunosuppressive, but have well-known adverse effects on many organ systems including progressive loss of bone density. Therefore, transition to steroidsparing agents is planned early in the therapeutic course. If response to the immunosuppressive and antiinflammatory systemic agents is insufficient, other agents such as intravenous immunoglobulin (IVIg), rituximab, or plasmapheresis may be considered (Mutasim, 2004).
Wound care is an important component of the treatment plan. Hydrating, occlusive dressings prevent excessive fluid and electrolyte loss in extensive disease, and promote healing. Erosions and ulcerations should be treated with clean warm water compresses twice a day followed by application of antibiotic or hydrophilic ointment and gauze wraps. Eschar or crust formation should be prevented since they slow healing and encourage infection. The prevention of secondary bacterial infection, which can lead to sepsis, is essential. Finally, pressure ulcers may be avoided in bedridden patients with frequent position changes.
Conclusion
The autoimmune bullous dis eases are mediated by autoantibody production to cutaneous adhesion molecules. Diagnosis is based on a combination of clinical, histopathological, and immunofluorescence features. Current treatment regimens have greatly reduced mortality, but morbidity is often significant. There is no means of prevention. Wound care should be employed to decrease secondary complications such as bacterial infection and sepsis as well as promote healing.
This article and the CE answer/ evaluation form are also available online at www.dermatologvnursing.net
Publisher’s Note: Publication of this article was supported by a grant provided by Nurse Competence in Aging, a 5-year initiative funded by The Atlantic Philanthropies (USA) Inc., awarded to the American Nurses Association (ANA) through the American Nurses Foundation (ANF), and representing a strategic alliance between ANA, the American Nurses Credentialing Center (ANCC), and the John A. Hartford Foundation Institute for Geriatric Nursing, New York University, The Steinhardt School of Education, Division of Nursing.
For more information, contact the John A. Hartford Foundation Institute for Geriatric Nursing, New York University, The Steinhardt School of Education, Division of Nursing, 246 Greene Street, 5th Floor, New York, NY10003, or call (212) 998-9018, or email [email protected] or access the Web site at www.hartfordign.org
References
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Beutner, E.H., Chorzelski, T.P., & Kumar, V. (1987). Immunopathology of the skin (3rd ed.). New York: John Wiley & Sons.
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Liu, Z., Giudice, GJ., Zhou, X., Swartz, S.J., Troy, J.L., Fairley, J.A., et. al. (1997). A major role for neutrophils in experimental bullous pemphigoid. Journal of Clinical Investigations, 100, 1256-1263.
Mutasim, D.E. (2004). Management of autoimmune bullous diseases: Pharmacology and therapeutics. Journal of the American Academy of Dermatology, 51, 859-877.
Mutasim, D.E, & Diaz, L.A. (1991). The relevance of immunohistochemical techniques in the differentiation of subepidermal bullous diseases. American Journal of Dermatopathology, 13, 77-83.
Mutasim, D.E, Pelc, N.J., & Anhalt, G.J. (1993a). Cicatricial pemphigoid. Dermatologic Clinics, 77(3), 499-510.
Mutasim, D.E, Pelc, N.J., & Anhalt, G.J. (1993b). Paraneoplastic pemphigus, pemphigus vulgaris, and pemphigus foliaceus. Clinics in Dermatology, 77, 113-117.
Mutasim, D.E, Pelc, N.J., & Supapannachart, N. (1993). Established methods in the investigation of bullous diseases. Dermatologic Clinics, 11, 399-418.
Jill B. McCuin, MD, is a Dermatology Resident, University of Cincinnati Medical Center, Cincinnati, OH.
Terri Hanlon, BSN, RN, is Director of Practice Operations, Department of Dermatology, University of Cincinnati, Cincinnati, OH.
Diya F. Mutasim, MD, is Professor and Chairman, Department of Dermatology, University of Cincinnati Medical Center, Cincinnati, OH.
Copyright Anthony J. Jannetti, Inc. Feb 2006
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