Bullous Pemphigoid in a Patient with Systemic Sclerosis (Scleroderma)

To the Editor:

A 65-year-old Caucasian man with scleroderma presented for evaluation of 6 months of intense pruritus and recurrent cutaneous ulcerations. He began to develop ulcerated lesions on both the upper and lower extremities thought to be secondary to self-inflicted trauma from scratching areas of dry thickened scleroderma skin. Several times, these lesions became secondarily infected and required topical and systemic antibiotic therapy. It was noted that the ulcers seemed to respond to topical application of triamcinolone 0.1% cream.

Examination on presentation revealed diffuse cutaneous sclerosis with taut scaly skin over the dorsum of the hands, face, arms, trunk, and legs. Superimposed on areas of scleroderma skin were multiple papules, becoming confluent in some areas. The papules were erythematous with fine overlying scale and areas of lichenification. Well demarcated punched-out ulcerations were also present, particularly over the lower extremities (Figure 1). Mucous membranes and conjunctivae were normal. No bullae were present on examination, but he reported previously noting thin blisters on his legs.

H&E staining of the biopsy specimen from the right shoulder revealed acute spongiotic dermatitis with focal substitutive collagenosis, consistent with nonspecific eczematous change superimposed on scleroderma. Direct immunofluorescence performed on the biopsy specimen showed heavy linear deposition of IgG and C3 along the basement membrane zone (Figure 2), a finding that is diagnostic for bullous pemphigoid. He was given mycophenolate mofetil 1 g PO bid, and the prednisone was increased to 50 mg PO qam for 4 weeks before being reduced back to 40 mg PO qd. He responded to this therapy with improved pruritus, healed ulcerations, and resolution of papules. He currently is doing well with inactive pemphigoid skin disease, taking mycophenolate mofetil 1 g PO bid and prednisone 5 mg PO qod.

Although a case of a 73-year-old woman with generalized morphea who developed bullous pemphigoid after receiving whole-body UVA-1 phototherapy is reported¹, the coexistent systemic sclerosis (scleroderma) with bullous pemphigoid is not described in the literature.

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Figure 1. Bullous pemphigoid causing multiple ulcerations in the sclerotic skin on the extremity of a patient with scleroderma.

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Figure 2. Direct immunofluorescence performed on the biopsy specimen showing heavy linear deposition of IgG and C3 along the basement membrane zone, a finding that is diagnostic for bullous pemphigoid.

Bullous pemphigoid is an autoimmune bullous skin disease affecting keratinocytes' adherence to each other and to the basement membrane. Autoimmune bullous diseases with blistering at the intraepidermal level are in the pemphigus group (pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus), while blistering occurring at the subepidermal level is classified as pemphigoid disease (bullous pemphigoid, gestational pemphigoid, and cicatricial pemphigoid). Bullous pemphigoid has primary cutaneous involvement, gestational pemphigoid (also known as herpes gestationis) has primary cutaneous involvement in pregnant women, while cicatricial pemphigoid has primary mucosal involvement².

Clinically, bullous pemphigoid presents with cutaneous lesions, with only rare mucosal involvement. Disease progression typically begins with urticarial plaques or papules, erythematous macules, or, as in our case, eczematous lesions, all of which are usually intensely pruritic³. Tense clear blisters then develop over an erythematous base, which may manifest as an extensive bullous eruption².

Direct immunofluorescence findings are diagnostic for bullous pemphigoid. On biopsy of normal-appearing skin adjacent to a lesion, direct immunofluorescence reveals deposition of IgG and C3 along the epidermal basement membrane zone. Deposition of C3 is characteristically more intense than that of IgG³. While direct immunofluorescence is 100% sensitive, indirect immunofluorescence is approximately 90% sensitive when salt-split human skin is used as a substrate for circulating bullous pemphigoid autoantibodies. These antibodies bind to the epidermal roof³. Biopsy histology shows epidermal blistering with prominent polymorphonuclear and eosinophilic infiltrates². Bullous pemphigoid is triggered by autoantibody formation against the BP180 antigen, also known as Type XVII collagen. BP180 antigen is a key component of epidermal hemidesmosomes, and is a transmembrane protein composed of a short noncollagenous ectodomain adjacent to the plasma membrane as well as a long collagenous endodomain that interacts with the basement membrane's anchoring proteins. Pathogenic autoantibodies in bullous pemphigoid recognize an immunodominant epitope in the ectodomain of BP180 antigen². Antibody activation against BP180 antigen leads to complement activation, resulting in neutrophil and eosinophil infiltration. Protease release from neutrophils is likely the critical step in subepidermal blister formation².

Prednisone has been a mainstay of treatment, with rapid effects seen at 0.5–1 mg/kg PO qd⁴. Antibiotic therapy can also have effective antiinflammatory effects as part of a steroid-sparing strategy³. Newer data suggest that mycophenolate mofetil 1 g PO bid may be exceedingly useful in limiting steroid usage while inducing prompt and persistent remission of bullous pemphigoid⁵.

Diagnosis of blistering skin disease like bullous pemphigoid can be overlooked in patients with scleroderma because significant pruritus and ulcerations are commonly part of the scleroderma skin process. Our case demonstrates that bullous pemphigoid should be considered when evaluating scleroderma patients with diffuse papules, lichenified lesions, blistering, or ulcerations. It also illustrates the unique concurrence of 2 rare autoimmune diseases.

We describe a case of bullous pemphigoid in a man with systemic sclerosis (scleroderma) skin disease, who when diagnosed correctly responded to appropriate therapy.

NOELLE S. SHERBER, MD, Johns Hopkins University School of Medicine; FREDRICK M. WIGLEY, MD, Departments of Rheumatology and Medicine; GRANT J. ANHALT, MD, Departments of Dermatology and Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Address reprint requests to Dr. F. Wigley. E-mail: fwig@jhmi.edu

REFERENCES

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2. Nousari HC, Anhalt GJ. Pemphigus and bullous pemphigoid. Lancet 1999;354:667-72.

3. Mutasim DF, Anhalt GJ. Bullous diseases in the elderly. Clin Geriatr Med 2002;18:43-58.

4. Nousari HC, Griffin WA, Anhalt GJ. Successful therapy for bullous pemphigoid with mycophenolate mofetil. J Am Acad Dermatol 1998;39:497-8.

5. Nousari HC, Sragovich A, Kimyai-Asadi A, Orlinsky D, Anhalt GJ. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999;40:265-8.