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Presentation

       A 63-year-old white woman presented with a rash on all extremities and the face, conjunctivitis, and painful perioral and oral mucosal erosions. She denied pharyngeal or esophageal dysphagia. The patient was afebrile and denied weakness, malaise, or other constitutional symptoms. Her past medical history was significant for lung cancer, diagnosed 1 year prior to presentation, which was currently in remission. The patient also had a past medical history of dry eye syndrome and hypertension. She underwent initial chemotherapy followed by maintenance therapy with gefitinib (Iressa, AstraZeneca Pharmaceuticals LP, Wilmington, Del) 250 mg/day, a medication indicated for treatment of non-small-cell lung cancer,¹ and had been taking this medication for 7 months at the time of presentation to the dermatology clinic. She was also on cyclosporine ophthalmic drops (for dry eye syndrome), verapamil, atenolol, and hydrocortithiazide/triamterene (for hypertension). Her only known drug allergy was to trimethoprim and sulfamethoxazole.

Physical Examination

       On examination, the patient had multiple erythematous papules and plaques up to 1.5 cm in diameter on the extensor aspect of all extremities with greater involvement of the arms than legs. Two erythematous pruritic pustules were noted on the dorsum of the right hand. Palms and soles were spared. The facial exam was significant for periorbital erythema with severe conjunctivitis bilaterally and multiple skin lesions. Erythematous 3–6 mm papules, some with excoriations, were found on the nose, lateral cheeks, and ears. Perioral lesions consisted of papules, pustules, small erosions with erythema and crusting of the lips, and lateral commissures. There were 2 shallow 1 cm x 2 cm plaques of leukoplakia on the dorsal tongue. The gingivae were erythematous and edematous with < 1 mm white spherical lesions at the gingival border of the lower jaw. The patient also had generalized xerosis. No lymphadenopathy was noted (Figures 1–3).

Figure 3

Figure 2

Periorbital erythema with severe conjunctivitis and multiple erythematous papules on the nose and around the mouth.

Figure 1

Laboratory Values

       Blood work revealed leukocytosis and thrombocytosis. Blood urea nitrogen (BUN) was 37, and creatine (Cr) was within normal limits. Sedimentation rate was 38, C-reactive protein (CRP) was within normal limits, and antineutrophil cytoplasmic antibodies (C-ANCA and P-ANCA) were negative.
       Biopsies were taken of a pustule on the dorsal right hand and submitted for histopathology and direct immunofluorescence. The histopathology report for the right arm revealed orthokeratosis, focal spongiosis, neutrophilic exocytosis, papillary dermal edema, interstitial neutrophilic infiltrate, and extravasated erythrocytes. The report for the left arm revealed interface dermatitis and perivascular/interstitial mixed inflammatory cell infiltrate (lymphocytes and neutrophils).
       A direct immunofluorescent (DIF) report revealed linear IgG at the dermal-epidermal junction. Results of an indirect immunofluorescent (IIF) report are shown in Table 1.

Table 1

Diagnosis

       The patient was diagnosed with bullous pemphigoid. Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies to the BP230 and BP180 hemidesmosomal proteins in the epidermal basement membrane, which stimulate a cascade of complement and inflammatory mediators.² Bullous pemphigoid occurs most often in the elderly at an average age of 65 years, presumably due to immune senescence in the skin.³ There are idiopathic and drug-induced forms that manifest as the classic tense bullous eruption or localized, nodular, vegetating, erythrodermic, eczematous, or erosive lesions.⁴ Mucosal involvement has been found in only in 8–39% of cases.⁵ Drugs previously reported to cause BP include penicillins, furosemide, nonsteroidal anti-inflammatory drugs (NSAIDs), captopril, phenacetin, penicillamine, and terbinafine.^4,6,7
       According to 1 report, the subtype of benign mucous membrane pemphigoid may be associated with lung cancer.⁸ In a series of 1,113 documented cases of BP in Japan, 5.8% were associated with internal malignancies as compared to 0.61% of age-matched controls, although the most common malignancy was gastric cancer.⁹ The authors believed the patient was in remission from cancer at the time she developed BP, which suggests either an undetected relapse or another predisposition to BP, possibly from gefitinib therapy. Human squamous cell carcinoma, a subtype of non-small-cell lung cancer, is characterized by abnormal expression and distribution of BP180,¹⁰ which may underlie a mechanism for carcinogenesis and also predispose the patient to developing autoimmunity to BP180.

Immunopathology

       Autoantibodies in BP target the BP230 and BP180 antigens, which are located in the hemidesmosomal complex of the skin basement membrane zone.² Autoantibodies detected in patients with BP are probably pathogenic as indicated by both in-vivo and in-vitro models of disease.¹¹ Subsequent complement activation recruits chemical and cellular immune mediators to the skin, ultimately resulting in blister formation.² Ultrastructural studies demonstrate that early blister formation in BP occurs in the lamina lucida between the basal call membrane and the lamina densa.¹² Both autoantibodies and complement may be detected by various immunofluorescent, immune electron microscopy, and molecular biology techniques.²
       Direct immunofluorescence. Direct immunofluorescence of perilesional skin from pemphigoid patients reveals immunoreactant deposited in a lineal pattern at the epidermal basement membrane.^13,14 IgG is detected in most patients with BP; IgG4 is the predominant subclass followed by IgG1.¹⁵ However, IgD, IgE, or IgA can be found in association with IgG at the basement membrane.¹⁶
       Indirect immunofluorescence (IIF). Indirect immunofluorescence indicates that about 70 to 80% of patients with BP are found to have circulating IgG that bind to the basement membrane of normal stratified squamous epithelia, such as human epidermis or monkey esophagus. Most patients with circulating anti-basement membrane IgG also have anti-basement membrane IgG in their sera.^16,17 In contrast to pemphigus, in BP the IIF antibody titer does not usually correlate with disease extent or activity.¹⁷ If the immunofluorescence substrate is incubated first in 1M NaCl to separate the epidermis from the dermis at the lamina lucida, an even higher percentage of patients will have detectable circulating antibody.¹⁶ This IIF method is more sensitive for detection of circulating anti-basement membrane zone antibodies when NaCl-separated skin rather than intact human skin is employed as substrate.¹⁸ In addition to increased sensitivity, the other advantage of this “salt split” substrate is that BP antibodies bind to the roof of the artificially induced blister and thus can be differentiated from the antibodies of patients with epidermolysis bullosa aquisita, whose antibodies bind to the floor of the blister.¹⁸

Management

       With a preliminary clinical diagnosis of erythema multiforme or Stevens-Johnson syndrome from gefitinib therapy and oral/perioral candidiasis with possible bacterial or viral conjunctivitis, the patient was started empirically on oral acyclovir, clotrimazole, nystatin cream for external perioral candidiasis and perleche, erythromycin ophthalmic ointment, and palliative anesthetic mouthwash containing lidocaine, aluminum hydroxide/magnesium hydroxide, and diphenhydramine. Gefitinib was discontinued under the care of the patient’s oncologist, and biopsies were obtained for histopathology and direct immunofluorescence. The diagnoses of paraneoplastic pemphigus and bullous lupus erythematosus were also considered.
       At the follow-up visit, based on the aforementioned histopathology and direct immunofluorescence report, the authors narrowed the differential diagnosis down to acute febrile neutrophilic dermatosis (Sweet’s syndrome), bullous pemphigoid with atypical clinical presentation, bullous lupus erythematosus, and a possible drug eruption. At this point, another sample for IIF was sent to Beutner Laboratory Inc. (Buffalo, NY).
       The IIF report, the predominance of IgG4 and strongly positive anti-basement membrane zone antibodies, and the DIF report of linear IgG at the dermal-epidermal junction are highly suggestive of BP^14,15 with atypical clinical presentation. Bullous pemphigoid with nonclassical papular, vesicular, herpetiform, pustular, and/or eczematous clinical presentation has been reported in the literature, especially in association with antibodies directed at dermal antigens, such as 200 kDa.¹⁹ The classical antigens of BP—BP180kDa and BP230kDa—are well known. Immunoprecipitation studies have reported the presence of antibodies including 170kDa and 200kDa protein.^20,21 Immunoprecipitation would be the next step to confirm that specific antigen.²⁰ However, since all BP patients respond very well to immunosuppression therapy, immunoprecipitation is usually applied for academic purposes rather than clinical management. There have been few reports of possible associations between BP and malignancies.^9,10 However, malignancy-associated or paraneoplastic BP remains a controversial issue.
       Considering positive anti-basal cell cytoplasm IgG and IgG4 and weakly positive anti-nucleotide antibody (ANA), it would be difficult to rule out the possibility of drug eruption.²² However, none of the patient’s medication was known to cause such cutaneous manifestations. The inflammation caused by initial pathogenic antibodies of BP may damage the basal cells and, as a result, may lead to secondary non-pathogenic antibodies in these patients. However, the manufacturer of gefitinib reports that the most common side effects are diarrhea, rash (morphology not specified), acne, dry skin, nausea, and vomiting, which usually present within the first month of therapy. One percent of 941 patients in clinical trials and 23,000 patients in the “Expanded Access Program” experienced conjunctivitis, while 1% experienced a vesicobullous rash, and 1% had mouth ulceration.²³
       The patient refused to give another blood sample for analysis of double strand DNA to further investigate the possibility of bullous lupus erythematosus. However, a weakly positive ANA is not suggestive of this diagnosis.
       Negative intercellular Abs and desmoglein 1 and 3 in IIF and ELISA studies ruled out the diagnosis of paraneoplastic pemphigus and pemphigus vulgaris, respectively. Finally, based on available laboratory results and the patient’s clinical course, the rare possibility of coexisting BP with Sweet’s syndrome cannot be excluded.

Patient Management

       The patient was started on prednisone 60 mg/day with gradual tapering. The clinical response was rapid and satisfactory. In the course of 6 months follow-up, no new skin lesions or evidence of cancer recurrence were found.