Bullous pemphigoid

Abstract

Cicatricial pemphigoid is a chronic, systemic, autoimmune disease characterized by progressive bullous skin and mucous membrane lesions that tend toward scarring and involution. Manifestations of cicatricial pemphigoid include oral mucosal bullous lesions in 85 to 90% of patients, ocular mucosal lesions in 66%, nasal mucosal lesions in 15 to 23%, and laryngeal involvement in 8 to 21%. We report five cases of cicatricial pemphigoid in which all patients had ENT manifestations--specifically, oral and nasal mucosal involvement. Three of these patients also had laryngeal lesions; one of the three had a large laryngeal ulceration and bullae that caused a laryngeal stenosis and necessitated a tracheostomy. In addition to the five case reports, we also review the literature and discuss the pathogenesis, diagnosis, and treatment of this uncommon disease.

Introduction

Cicatricial pemphigoid is a chronic, systemic, autoimmune, bullous disease. It is characterized by progressive bullous skin and mucous membrane lesions that tend toward scarring and involution. Its incidence is unknown, but it is relatively rare. When it does occur, it is more common in women than in men by a ratio of 2:1; most affected patients are in the fifth or sixth decade of life. (1,2) Its distribution is universal-that is, there is no geographic or racial predominance. Histologically, cicatricial pemphigoid is characterized by the formation of subepithelial bullae that contain lymphohistiocytic infiltrates and a small number of eosinophils.

Electron microscopy of cicatricial pemphigoid lesions typically shows that the bullae are located between the basal cell membrane and the basal lamina. In 70% of cases, direct immunofluorescence of a lesion will reveal the presence of a linear antibasal membrane pattern, predominately represented by immunoglobulin G (IgG). (1-3) The oral mucosa is the most frequently affected site (85 to 90% of patients), followed by the ocular mucosa (66%).2 The upper airway and digestive tract are also affected in a considerable number of patients. Nasal involvement has been reported to occur in 15 to 23% of patients and laryngeal involvement in 8 to 21%. (4,5)

In this article, we describe five cases of clinical cicatricial pemphigoid that featured otorhinolaryngologic manifestations-that is, all patients exhibited involvement of the oral, nasal, and ocular mucosae. Three of these patients had laryngeal lesions, one of whom had severe lesions that led to stenosis that necessitated a tracheostomy. We also present an extensive discussion of the literature on this subject.

Case reports

Patient 1. A 42-year-old white man was seen at the otolaryngology first-aid station at our institution for evaluation of signs of upper respiratory failure, which required an emergency tracheostomy. His symptomatology included a progressive and continuous dysphonia of 2 years' duration and a productive cough. He had a 10-year history of vesiculobullous lesions of the scalp and trunk and a 5-year history of recurrent epistaxis and nasal obstruction following surgery for acquired urethral dilation.

On physical examination, the scalp and trunk were noted to exhibit segmental alopecia along with cicatricial and crusted lesions. Oroscopy revealed the presence of a shallow 1 x 1-cm ulcer with regular borders in the soft palate. Inspection of the nasal cavity revealed the presence of an abundant crust, a septal perforation with regular borders, and synechia between the middle concha and the septum. Direct laryngoscopy detected vesiculobullous lesions at the lingual face of the epiglottis, posterior synechia in the supraglottic region, edema, and diffuse hyperemia of the larynx. Bronchoscopy detected small, shallow ulcers of the bronchial mucosa. The patient also had conjunctival hyperemia and ectropion.

Findings on analysis of biopsy specimens of the skin and oral cavity lesions were consistent with cicatricial pemphigoid. The patient was treated with prednisone and methotrexate, and his condition improved. He remains stable on maintenance treatment with low-dose prednisone. His tracheostomy remains.

Patient 2. A 35-year-old black man complained of symptoms of bilateral mucopurulent rhinorrhea. He had a 3-year history of crust formation and nasal obstruction. He also reported recurrent ulcerated lesions in the oral cavity and two bullous lesions (one on his leg and one on his penis) that had rapidly involuted. He also reported a dry-eye sensation.

Physical examination of the eyes revealed bilateral conjunctival hyperemia and synechiae. Oroscopy detected a shallow, erythematous, 3-cm ulcerated lesion on the left jugal mucosa. On nasal examination, abundant crusts and a purulent secretion were present in the nasal fossa, but no ulcers or bullae were found. Findings on laryngologic examination were normal.

A biopsy analysis of the oral lesion yielded findings compatible with cicatrical pemphigoid. The patient was started on prednisone and cyclophosphamide; maintenance therapy has resulted in a partial resolution of the lesions.

Patient 3. A 74-year-old man reported a 4-year history of erythematous and violaceous skin lesions on his trunk and arms; the lesions were covered with crusts. His symptoms had progressed slowly, and they eventually led to atrophy of the affected skin. The man also had erythematous and ulcerated lesions in his genital region. Other symptoms included epistaxis, nasal obstruction, conjunctival hyperemia, and significant lacrimation. The patient said he was thinning and that his overall state of health was worsening.

On examination of the nasal cavity, bullous and bleeding lesions without crusts were observed. Oroscopy detected shallow ulcers on the palate and jugal mucosae. Findings on laryngeal examination were normal. Inspection of the eyes revealed conjunctival hyperemia and bilateral palpebral synechiae.

A biopsy analysis of one of the skin lesions confirmed the diagnosis of cicatricial pemphigoid. The patient was started on cyclosporine and prednisone, but he died shortly thereafter as a result of complications of the poor state of his general health and the side effects of the medications.

Patient 4. A 37-year-old black man with a 4-year history of conjunctival hyperemia and eye secretions sought treatment for crusted nasal lesions and bilateral mucopurulent secretions. He also had bullous lesions on his leg and penis.

Findings on biopsy of the jugal and nasal mucosae were compatible with cicatricial pemphigoid. Treatment with prednisone and cyclophosphamide was unsuccessful and led to microcytic anemia as a side effect. The patient later developed bilateral ocular synechiae and dysphonia. Direct laryngoscopy detected scarified lesions and edema of the vestibular folds. Burst therapy was started with cyclosporine, which led to an apparent remission of the disease activity.

Patient 5. In 1993, a 49-year-old white woman experienced an episode of nasal obstruction, nasal crusts, nasal bleeding, and painless ulcerated oral and vaginal lesions. The lesions resolved in 2 days, but she began to experience bilateral conjunctival hyperemia and xerophthalmia. She was incorrectly diagnosed with possible Behcet's disease and started on prednisone and colchicine, but she did not respond well.

In 1995, the patient came to our service for evaluation of dyspnea and laryngeal rales. Flexible laryngoscopy detected arytenoid edema and ulcerated lesions. Biopsy samples of the nasal and oral mucosae were consistent with cicatricial pemphigoid. The disease was being controlled with chiorambucil, but the patient stopped taking the drug. Ten months later, the disease recurred, this time accompanied by conjunctival synechia. Laryngoscopy detected epiglottic lesions and areas of supraglottic cicatrical bridles. The patient refused to take the medication we prescribed.

In 1998, the patient began to experience anew outbreak of oral and cutaneous lesions. She was restarted on chiorambucil and referred for phonotherapy to improve her vocal performance.

Discussion

Hippocrates was the first to describe pemphigoides pyretoi as a type of fever accompanied by blisters. (6) In 1793, Wichmann was the first to report pemphigoid that affected the conjunctiva. (7) In 1857, Cooper was the first to adequately describe cicatricial pemphigoid of the eye, which he called conjunctival pemphi goid. (8) In 1879, Von Graefe was the first to describe the clinical signs, symptoms, and consequences of cicatricial pemphigoid. (9) In 1953, Lever delineated the clinical and histopathologic differences between pemphigoid and pemphigus. (10) In the past century, terminology has evolved to describe the different types of disease: ocular pemphigus, (11) ocular cicatricial pemphigus, (12) essential retraction of the conjunctiva, (13) and benign pemphigoid of the mucous membranes. (14)

Cicatricial pemphigoid is a systemic disease with both ocular and extraocular manifestations. (2) It is characterized by bullae of the subepidermal skin and mucous membranes. A scar generally occurs, which can cause an irreversible loss of function at the affected site. Cicatricial pemphigoid typically affects patients between the ages of 40 and 60 years. Patients usually exhibit vesiculobullous ulcerated lesions in the oral, genital, and conjunctival mucosae. Cicatricial pemphigoid differs from bullous pemphigoid in that the former is characterized by the presence of a scar secondary to the bulla. Another characteristic of cicatricial pemphigoid that is important in the differential diagnosis is the early occurrence of oral lesions. (2)

Pathogenesis. The pathogenesis of cicatricial pemphigoid involves a defect in immunoregulation and a resultant production of autoantibodies that affect the basal membrane. The deposition of autoantibodies occurs as a result of the activation of the complement cascade, which leads sequentially to chemotaxis of inflammatory cells, degranulation, fibroblast activation, cicatrization, and fibrosis. It is believed that patients with cicatricial pemphigiod have a genetic predisposition for the HLADQw7 gene. (2,15) Molecular and immunohistochemical studies have shown that laminin-5, a basal membrane glycoprotein, is one of the most prominent autoantigens in cicatricial penphigoid. (16,17) However, an absence of antilaminin-5 autoantibodies does not exclude a diagnosis of cicatricial pemphigoid. Patients with ocular manifestations have been found to have autoantibodies against the laminin-5 receptor 205-kDa beta-4 integrin, which is part of alpha-6-beta-4 integrin. (18) The development of a molecular definition of t hese autoantigens would make it easier to classify and characterize those subgroups of patients with cicatricial pemphigoid who have multiple clinical manifestations.

As mentioned, the complement cascade activates autoantibodies and chemotactic factors, which leads to cell degranulation. Basal membrane injury is probably mediated by proteases, which are originated by cell degranulation and which cause the dermis and epidermis to separate. This theory of bulla formation is based on both in vitro (19,20) and in vivo (12) studies. Other studies have shown that patients with cicatricial pemphigoid have low interIeukin-6 levels and high titers of tumor necrosis factor; the latter are associated with the activity status of the disease. (2,22,23)

Signs and symptoms. Most patients with cicatricial pemphigoid manifest oral involvement (desquamative gingivitis), which can progress to the development of a residual scar in the buccal cavity (figure 1). Erosions, which heal slowly, can affect the nasopharynx, conjunctiva, larynx, genitalia, and esophagus. Ocular involvement has been reported to cause blindness in 25% of patients (figure 2). (2) The earliest ocular manifestation is chronic conjunctivitis, which is sometimes accompanied by dry eye, burning, and/or a foreign-body sensation.

Two types of skin lesion can occur. The most common appears as a generalized, short-lived bullous eruption. The other is a localized erythematous plaque at the site of the bulla that can give rise to a scar. However, cutaneous involvement is not as common as mucosal involvement; when it does occur, it usually does so on the face, scalp, neck, inguinal areas, and limbs. Nasopharyngeal involvement is characterized by rupture of the vesicles in the nasal mucosa, rhinorrhea, crust formation, and epistaxis, all of which can eventually culminate in cicatricial stenosis. Pharyngeal involvement can cause dysphagia. Lesions in the respiratory tract can cause dysphonia, dyspnea, and laryngeal stenosis, and they can affect the vocal folds. More severe symptoms can lead to stenosis of the urethra, genitourinary tract, esophagus, and rectum. (1-3,5)

The primary lesion is a blister of variable size that ruptures in 24 to 48 hours. Following rupture, the skin surface is denuded and becomes covered with fibrin. The site eventually re-epithelializes and cicatricial tissue forms. All five of our patients exhibited a ruptured blister at the time of their initial examination, and all five had involvement of the oral mucosa. The oral mucosa--particularly the gingiva and jugal mucosa--is the most frequently affected site (85 to 90%). (2) Desquamative gingivitis can lead to bone resorption and the need for tooth extraction. Lesions of the buccal cavity can be accompanied by cicatricial involution.

The conjunctival mucosa is the second most frequently involved site (66%); most patients have bilateral involvement. (2) Severe ophthalmologic consequences are common. Reddish and flaccid vesicles, xerosis, symblepharon, and conjunctival scars can appear. Entropion, trichiasis, and corneal opacification can also occur. (13) The ocular manifestations in all five of our patients led to visual deficits and corneal scarring.

Cutaneous lesions are observed in 10 to 30% of patients. (3) Cutaneous lesions are tense bullae, sometimes similar to those seen in bullous pemphigoid; some patients experience cicatricial involution. Cutaneous lesions usually affect the face, scalp, neck, inguinal areas, and limbs; generalized lesions can also occur. There are two types of lesion. The more common is an inconspicuous bulla that resolves in a short time. The other is marked by an extensive erythema where the vesicle develops, and it tends to persist for a long period of time before it atrophies. We observed the latter type in patients 1 and 3.

The upper airway and digestive tract are affected in a considerable number of patients (figure 3). The sites of involvement, in decreasing order of frequency, are the nasal mucosa (15 to 23%), the pharynx (20%), the larynx (8 to 21%), and the esophagus (1 to 8%). (2,4,5) This type of pemphigoid can be fatal if stenosis develops in the esophagus or trachea. (3)

In patients with nasal involvement or chronic serous or serous or seroanguineous rhinorrhea, crust formation can occur and result in scar formation and stenosis. Extensive involvement of other parts of the upper airway and digestive tract usually occurs, as well.

When pemphigoid affects the pharynx, patients tend to experience sore throat, dysphagia, and odynophagia. Lesions typically appear as multiple shallow ulcers; the bullae are rarely visualized. Pharyngeal involvement can culminate in glottic stenosis (figure 4).

Laryngeal lesions usually appear as bullae and ulcers in the epiglottis (figure 5); other laryngeal sites can be affected, as well. These lesions are generally accompanied by lesions in the upper airway and digestive tract; only rarely are lesions limited to the larynx. These patients manifest dysphonia, odynophagia, and a progressive dyspnea. The disease course can progress to obstruction of the upper airways and require a tracheostomy (which occurred in our patient 1); in such cases, additional examination (e.g., bronchoscopy) is necessary. (4)

Cicatricial pemphigoid can involve other areas of the body, including the penis, anus, vagina, and urethra. (1)

Diagnosis. The diagnosis is based on clinical findings and confirmed by conventional histology and direct immunofluorescence. The histologic characteristic of pemphigoid syndromes is a subepidermal blister that contains a mixed infiltrate of numerous eosinophils, mononuclear cells, and some neutrophils. Direct immunohistologic examination of cicatricial pemphigoid biopsy specimens will detect complement and antibasal-membrane autoantibodies. (1,2) Direct immunofluorescence of the epithelium will demonstrate a linear and homogeneous pattern of IgG and C3 deposition in the basal membrane. The sensitivity of isolated immunofluorescence is approximately 50%.

The histopathologic diagnosis can be difficult, especially if the biopsy specimen does not contain a sufficient amount of stroma adjacent to the lesion. A false-positive immunohistochemical finding occurs in 20 to 25% of cases. (2) When immunofluorescence findings are negative, a more sensitive (83%) alternative is immunoperoxidase staining. (2)

The differential diagnosis includes other causes of desquamative gingivitis and cicatricial conjunctivitis, which include pemphigus vulgaris, erythema multiforme, dermatitis herpetiformis, aphthous stomatitis, and Behcet's disease. (24)

In 1957, Brunsting and Perry described a type of cicatricial pemphigoid that was characterized by recurrent, circumscribed, chronically progressing vesicobullous eruptions of the head and neck that caused atrophic scarring. (25) The diagnosis of this type of pemphigoid is difficult because the skin lesions are inconspicuous and because immunofluorescence yields a high percentage of false-negative results. (26) Other clinical variants of cicatricial pemphigoid include localized oral, disseminated, and purely ocular disease. (27) It is also possible that cicatricial pemphigoid can be caused by other autoimmune diseases, such as Stevens-Johnson syndrome. (28,29)

Treatment. The treatment of cicatricial pemphigoid depends on the extensiveness of the bullae. Small and localized lesions can be controlled with local measures. Buccal lesions in particular respond well to topical steroids and local hygiene. However, most patients require systemic therapy, and corticosteroids are the drugs of choice. Immunosuppressants such as azathioprine, methotrexate, and cyclophosphamide--alone or in combination--have been used with success, (1,3) and they were the agents of choice for our five patients.

Topical therapy with a corticosteroid is indicated as the initial treatment for mild cases of cicatricial pemphigoid, and dapsone can be used for recurrences. Severe forms that do not respond to a sulfone can be treated with a combination of a systemic corticosteroid and an immunosuppressant. High-dose corticosteroids can control the cicatricial process, but they are not as effective as immunosuppressants and they can cause late complications after prolonged use.

Chemotherapeutic drugs inhibit inflammation and the progression of cicatrization in approximately 90% of patients. (30) Should initial therapy fail, azathioprine can be added to or substituted for the first drug. If the disease remains active, the physician can add cyclophosphamide. Patients with severe cases can be started on cyclophosphamide with or without prednisone; methotrexate can be used, as well. Cyclosporine is not very effective in treating ocular disease, but it does provide some benefit for patients with upper-airway involvement. Le Rouic et al reported that sulfasalazine was very effective in treating ocular disease. (30) Dragan et al proposed the use of tetracycline and niacinamide for elderly patients who cannot tolerate chemotherapeutic drugs. (31) Donnenfeld et al described the use of subconjunctival mitomycin C for the treatment of ocular involvement. (32) The toxicity of systemic immunosuppressants must be taken into account. Because recurrences have been reported in one-third of cases, al l patients must be followed up indefinitely. (2)

Surgical treatment is indicated for the removal of scars and stenosis; our patient 1 underwent surgery to correct his urethral stenosis. Surgery for stenosis is best performed when the disease is in remission. (1-3)

In conclusion, although cicatricial pemphigoid is a relatively uncommon disease, it should be included in the differential diagnosis of systemic diseases that are marked by otorhinolaryngologic impairment. Because treatment involves the use of drugs with important side effects, the collaboration of specialists in dermatology, oncology, and chemotherapy is ideal in order to obtain the best possible outcome. The five cases described here illustrate the importance of otorhinolaryngologist awareness of this disease in that the first manifestations in these patients were head and neck signs and symptoms.

References

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From the Stomatology Group. Division of Clinical Otolaryngology, Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo, Brazil.

Reprint requests: Ivan Dieb Miziara, MD, Rua Cristiano Viana, 450-apto. 121-Jd. America, Silo Paulo, Brazil 05411-970. Phone: +55-11-3085-2331; fax: +55-11-3085-1185; e-mail: miz@uol.com.br

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