Pyoderma gangrenosum in a patient with bullous systemic lupus erythematosus

ARTICLE

We report a 55-year-old woman with bullous systemic lupus erythematosus, who later developed pyoderma gangrenosum (PG). Dapsone was effective for the eruption of bullous bullous systemic lupus erythematosus but not for pyoderma gangrenosum. Cyclosporine was effective for the skin lesions of pyoderma gangrenosum. This is the first reported case of PG associated with bullous systemic lupus erythematosus.

Key words: bullous systemic lupus erythematosus, pyoderma gangrenosum, type VII collagen, cyclosporine.

Pyoderma gangrenosum (PG) usually appears as progressively enlarging, necrotizing, non-infectious ulceration of the skin. PG shows various clinical features, such as pustules, furuncle-like nodules, bullae, or vegetating lesions [1]. PG occurs in association with a number of systemic diseases, most frequently with inflammatory bowel diseases (IBD) [2, 3]. PG has also been seen in patients with arthritis [4], hematologic malignancies [5, 6] and chronic active hepatitis [7]. In this report, we describe the first case of PG associated with bullous systemic lupus erythematosus (SLE), in which autoantibodies against type VII collagen were confirmed.

Case report

A 55-year-old woman had a one-year history of autoimmune hemolytic anemia showing positive Coomb's test, positive antinuclear antibodies and hypocomplementemia. Administration of prednisolone (60 mg/day) started in April 1993. With the improvement of anemia, prednisolone was gradually tapered to 15 mg/day, and mizoribine, a novel immunosupressant, started on March 1994. Two days after the medication, an eruption developed on her trunk and upper extremities. Although mizoribine was discontinued, the rash spread to other sites of the body and the patient was hospitalized.

Physical examination revealed extensive exsudative erythema on her trunk and extremities (Fig. 1). Erosions in the oral cavity were also seen. In some lesions, vesicles developed in the erythemas and progressed to tense bullae. Laboratory tests exhibited reduced levels of serum complement components; C3, 40.7 mg/dl (normal range 55-120 mg/dl); C4, 6.1 mg/dl (normal range 20-50 mg/dl); and CH50, below 10 U/ml (normal range 29-48 U/ml). Serological studies demonstrated antinuclear antibodies at a titer of 1:640 with a homogeneous pattern, anti-DNA antibodies 26 IU/ml (normal range < 6 IU/ml), and anti-single strand DNA antibodies 66 IU/ml (normal range < 10 IU/ml). Anti-cardiolipin antibodies, immunoglobulin levels, blood cell counts and liver and kidney function tests were within normal limits.

Histological examination of the skin biopsy from the upper extremity showed a subepidermal blister with neutrophic infiltration in the upper dermis. A direct immunofluorescence (IF) demonstrated a linear deposition of IgG and IgA at the basement membrane zone. An indirect IF using normal human skin section showed circulating IgG anti-basement membrane zone antibodies, which reacted with MNaCl split skin. Immunoblot analysis using dermal extracts of EDTA-separated normal human skin revealed that IgG in the patient's serum reacted with the 290 kDa protein, type VII collagen, which was also reacted by control EBA sera. In contrast, by immunoblot analysis using epidermal extracts, this patient's serum did not show any specific reactivity, while control bullous pemphigoid (BP) sera showed clear reactivity with the 230 kDa and 180 kDa BP antigens in a various pattern.

According to these findings, the patient was diagnosed as bullous SLE. Although the dosage of prednisolone was raised to 60 mg/day, blisters continued to develop. Administration of dapsone (100 mg/day) resulted in a remarkable resolution of blisters and erythemas. The dosage of dapsone was gradually reduced to 25 mg daily for one year. During the tapering period, slight recurrences of mucosal erosions and erythemas on the upper extremities were occasionally noted.

In March 1996, the patient had erythematous nodules on her right shoulder and right upper chest and they developed to ulcer formation (Fig. 2). The skin lesions spread to the trunk and extremities. Repeated cultures showed no growth of bacteria, fungi or mycobacteria. A biopsy specimen from the ulcerative lesion of the upper chest revealed infiltration of neutrophils and mononuclear cells. From these findings the diagnosis of PG was made.

Administration of anti-bacterial agents and topical treatments with lysozyme chloride or tretinoin tocoferid were not effective. Dapsone (100 mg/day) showed no therapeutic effects on the ulcerative lesions. Finally, cyclosporine (150 mg/day) was initiated and later the dosage was increased to 450 mg. This regimen was very effective, and the skin lesions almost disappeared within 3 months.

Discussion

Bullous SLE is a specific subgroup of autoimmune blistering skin diseases. Gammon et al., defined a number of criteria for bullous SLE: 1) an acquired, widespread, nonscarring vesiculobullous eruption, 2) a subepidermal blister and acute, neutrophil-predominant inflammation in the upper dermis, and 3) immunoglobulin and complement deposition at the basement membrane zone [8]. Bullous SLE is divided into two subgroups [9]. Patients with the circulating antibody to type VII collagen are classified as type 1. The antibodies react with the 290 kDa protein on either immunoprecipitation of radiolabeled keratinocytes or Western immunoblotting using normal dermal extracts. Patients without the antibodies are defined as type 2. As the present case revealed the presence of antibodies binding to the 290 kDa type VII collagen, this case can be classified as type 1.

Direct IF staining showed linear depositions of IgG and IgA at the basement membrane zone. IgA deposition has been frequently reported in bullous SLE [8], and correlated with the occurrence of renal diseases [10]. In our case, the patient developed nephritis 3 years after the onset of bullous SLE.

There have been several reports of PG associated with SLE [2, 11, 12], with drug-induced SLE [13], and with the presence of lupus anticoagulant [14]. To the best of our knowledge, this is the first report of PG in a patient with bullous SLE.

Dapsone is known to be effective to various cutaneous diseases which are characterized by the presence of neutrophil infiltration and dapsone is also effective against bullous SLE. Although the mechanism of the therapeutic action is not fully understood, some studies speculated that dapsone may inhibit the response of neutrophils to some chemotactic stimuli [15]. Because there are some reports of PG treated successfully with dapsone [16, 17], we used dapsone for PG, as well as bullous SLE. In our case, dapsone was effective on the skin lesions of bullous SLE, but not on those of PG. Cyclosporine proved to be beneficial on the PG lesions of our case, like previous successful PG cases [18-20]. For the treatment of PG with SLE, steroid, chloroquine, salicylazosulfapyridine, or cyclosporine have been used in previous cases [18, 19]. The different response to dapsone in this case suggests different immunological pathogeneses between bullous SLE and PG.

Since these skin conditions are based on different pathogeneses, we now hypothesize an accidental association occurred in the present case.

References

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Article accepted on 30/5/02