Penicillamine dermatopathy with lymphangiectases. A clinical, immunohistologic, and ultrastructural study

The term penicillamine dermatopathy refers to the characteristic hemorrhagic skin lesions found in persons receiving long-term penicillamine therapy for either Wilson's disease or cystinuria. These lesions are thought to develop as a result of faulty collagen and elastin synthesis. We describe a patient with Wilson's disease who developed extensive penicillamine dermatopathy. In addition, histologic, immunochemical, and ultrastructural studies revealed multiple lymphangiectases with blood vessel to lymphatic anastomosis within these lesions, a finding not previously reported. The possible relationship to defective collagen and elastin formation are considered.     

Clinical and histological spectrum of elastotic changes induced by penicillamine

A 79-year-old-man with cystinuria requiring long-term penicillamine therapy presented with a 6-month history of itchy annular lesions in both axillae. Clinical examination revealed lesions consisting of crusted keratotic papules coalescing in an annular distribution. Associated findings included generalized skin laxity accentuated on the upper trunk and arms, as well as small yellowish papules on the neck. Histological evaluation revealed short, thick, eosinophilic elastic fibres with nodular protrusions. Transepidermal elimination of abnormal elastic fibres was also evident. We discuss the histological and clinical spectrum of penicillamine-induced elastotic changes and compare these changes to those seen in primary elastotic disorders.     

Reactions to Penicillamine: A Case of Cutis Laxa,Elastosis Perforans Serpiginosa and “Pseudo” Pseudoxanthoma

This patient was a 61‐year‐old white female who received several years of penicillamine therapy for the treatment of cystinuria. She subsequently developed penicillamine induced cutis laxa, elastosis perforans serpiginosa, and pseudoxanthoma elasticum like skin lesions. In addition, she suffered from numerous chronic bilateral lower extremity skin ulcerations. Her past medical history was also significant for end stage renal disease requiring hemodialysis and pulmonary fibrosis. She presented to the University of Miami Wound Care Center in 1/04 for treatment of her chronic ulcerations. On physical examination, the patient had multiple large hyperpigmented plaques with central ulcerations on her lower extremities. Some of the ulcers had overlying crust and others were covered with yellow fibrinous tissue. She also had generalized thickened, lax skin with multiple folds. On her neck, thighs, back and arms were violaceous, atrophic, serpiginous plaques with peripheral crusted erosions. A biopsy taken from the patients left thigh revealed dermal elastosis and the features of pseudo‐pseudoxanthoma. Two additional biopsies taken from the left thigh demonstrated elastosis perforans serpiginosa. This case highlights multiple skin manifestations of penicillamine therapy.     

Penicillamine-induced degenerative dermopathy in a patient with Wilson's disease

Penicillamine is a chelator that has been used in Wilson's disease, cystinuria, rheumatoid arthritis and heavy metal intoxication. We report a case of a 31-year-old man presented with skin atrophy, purpura and milia on the hips and shoulders after taking penicillamine for 1.5 years. According to literature review, this type of penicillamine-associated cutaneous adverse effect belongs to degenerative dermopathy, which mostly occurs on bony prominences and points of pressure in patients with Wilson's disease or cystinuria. Withdrawal or reduction of drug dose can improve the features of degenerative dermopathy.     

Induction of acantholysis in organ explant culture by penicillamine and captopril

Pemphigus is an autoimmune disease proved to be mediated by IgG autoantibodies. Skin lesions clinically and histologically identical to pemphigus may occur in patients receiving penicillamine and captopril, but some of these patients lack circulating or tissue-bound autoantibodies. Therefore, we examined the ability of these drugs to produce acantholysis directly in organ explant culture. Human skin explants were prepared from split-thickness graft skin from adults and from neonatal foreskins. Explants were cultured in media containing 0.1 to 200 mmol/L of penicillamine or captopril; parallel drug-free control cultures were also prepared. Acantholysis occurred in all split-thickness graft skin cultures incubated for 72 hours with at least 20 mmol/L of penicillamine and at 24 to 48 hours in those incubated with at least 10 mmol/L of captopril. Acantholysis occurred less frequently in foreskin cultures, being present in 1 (8%) of 12 of those exposed to at least 20 mmol/L of penicillamine and 3 (12%) of 25 of those exposed to at least 10 mmol/L of captopril. None of the parallel drug-free control cultures developed acantholysis. Subcorneal acantholysis, resembling that seen in pemphigus foliaceus, and suprabasilar acantholysis, resembling that seen in pemphigus vulgaris, were induced in vitro. Our results indicate that both drugs can act as ligands and produce acantholysis in organ explant culture in the absence of autoantibody. This ligand-induced acantholysis may also be responsible for induction of the disease in vivo in those patients who lack demonstrable autoantibodies.     

Acquired zinc deficiency disease of skin

Two patients, who were on long term parenteral hyperalimentation, developed skin lesions similar to those seen in acrodermatitis enteropathica. Both patients were treated with oral zinc sulphate and their skin lesions cleared completely. These patients are presented as an acquired zinc deficiency syndrome.     

Penicillamine-induced Elastosis Perforans Serpiginosa and Cutis Laxa in a Patient with Wilson's Disease

Elastosis perforans serpiginosa (EPS) is a rare reactive perforating dermatosis that is characterized by the transepidermal elimination of abnormal elastic fibers. Penicillamine, which is one of the clear triggers for EPS, is a heavy metal chelator that is primarily used for disorders such as cystinuria and Wilson''s disease. It may cause alterations in the dermal elastic tissue such as pseudo-pseudoxanthoma elasticum, acquired cutis laxa, EPS and anetoderma. Herein we present a case of cutis laxa and EPS in a 34-year-old man who was previously on a long-term, high-dose of penicillamine for Wilson''s disease. The combination of EPS and cutis laxa induced by penicillamine has rarely been reported and we report the first such case in Korea.     

Bullous Pemphigoid Induced by Penicillamine in a Patient with Wilson Disease

We report a 47-year-old man with Wilson disease who developed bullous lesions on the trunk and extremities after 20 years of penicillamine treatment. The histologic and immunofluorescence findings were diagnostic of bullous pemphigoid. When penicillamine was replaced by zinc sulfate, the patient’s bullous skin lesions improved rapidly. However, after 2 months of zinc sulfate treatment, the patient’s skin condition remained improved but his neurologic disease became worse and penicillamine was reinstituted. Bullous lesions recurred within 1 week and the diagnosis of penicillamine-induced bullous pemphigoid was confirmed. This is the first report of penicillamine-induced bullous pemphigoid in a patient with Wilson disease.     

D-penicillamine Induced Degenerative Dermopathy

D-penicillamine interferes with elastin and collagen metabolism and produces several cutaneous and multi-systemic side-effects. We present two cases of Wilson''s disease who on long-term penicillamine therapy developed drug-induced degenerative dermopathy manifesting as skin fragility over pressure sites and cutis laxa-like changes.     

Skin lesions induced by penicillamine. Occurrence in a patient with hepatolenticular degeneration (Wilson Disease).

A 41-year-old patient with hepatolenticular degeneration (Wilson disease), who had been treated for 15 years with penicillamine, developed small white papules at sites of venipuncture in the antecubital fossae and at surgical suture sites. Histologically, these papules showed focal areas of connective tissue degeneration in the dermis, but there was no evidence of inclusion cysts. The changes most likely resulted from the effect of penicillamine on new connective tissue formation at the sites of injury. The patient also developed crinkling of the skin of her face and neck while on the penicillamine regimen, and these changes were attributed, at least in part, to the effects of this drug on connective tissue.     

Chilblain lupus erythematosus of Hutchinson responding to surgical treatment: a report of two patients with anti-Ro/SS-A antibodies

We report two patients with chilblain lupus erythematosus of Hutchinson (CL) who responded to surgical treatment. One of them was a 72-year-old woman (case 1), and the other a 62-year-old man (case 2). We attempted to treat these patients by excising the lesions and subsequently performing full-thickness free skin grafting, using skin from the abdominal region. No recurrence was seen in the operated area 7 years (case 1) and 3 years (case 2) after surgery. However, lesions persisted in the areas not operated upon, and in the areas where lesions had not been adequately excised. These results suggest that surgical removal of local factors reduces the rash in these cases. In addition, both patients were serologically positive for the anti-Ro/SS-A antibody suggesting that local expression of the Ro/SS-A antigen may be involved in the pathogenesis of the skin lesions. To our knowledge, full thickness free skin grafting has not been used previously to treat CL-associated skin lesions, and is promising as a treatment for patients who do not respond to conventional means.     

Elastosis perforans serpiginosa and pseudoxanthoma elasticum-like skin change due to D-penicillamine

High dose D-penicillamine is used in the therapy of Wilson's disease and cystinuria. Elastosis perforans serpiginosa (Guilaine, Benhamou & Molas, 1972), penicillamine dermopathy (Sternleib & Scheinberg, 1964; Katz, 1967; Beer & Cooke, 1967), cutis hyperelastica (Charlebois, Cadotte & Barbeau, 1972), excessive skin wrinkling (Greer, Askew & Richardson, 1976) and pseudoxanthoma elasticum-like skin change (Meyrick Thomas et al., 1984) have all been documented as developing in consequence of such therapy. We report a patient in whom mild pseudoxanthoma elasticum-like skin change and elastosis perforans serpiginosa developed, following high dose D-penicillamine treatment for cystinuria.     

Systemic sclerosis-like lesions during long-term penicillamine therapy for Wilson''s disease

Systemic sclerosis-like lesions developed in a 14-year-old boy with Wilson's disease who had been treated with D-penicillamine for 11 years. Clinical and laboratory manifestations included proximal scleroderma, pulmonary restrictive defects, positive antinuclear antibodies, and the deposition of C3 at the dermal-epidermal junction of the lesional skin. This is the first case reported in which long-term administration of penicillamine was followed by the development of systemic sclerosis-like lesions.     

A case of penicillaminc-induced pemphigus, successfully treated by plasma exchange

Penicillamine, used for the treatment of rheumatoid arthritis, is known to induce severe side-effects on the skin resembling lupus en thematosus, epidermulysis bullosa, pseudoxanthoma elasticuni, elasiosis perforans serpinginosa and pemphigus-like dermatosis, which usually occur alter long-term therapy, Although rare, the pemphigus-like dermatosis is not always self-limiting and may persist for months after discontinuation of the drug. We report a patient who developed a pemphigus-like dermatosis after a year of treatment with penicillamine for severe seropositive rheumatoid arthritis. Despite daily therapy with 40 mg of prednisolone and 100 mg of azathioprine, skin lesions continued to appear for 18 months after discontinuation of penicillamine. Four plasma exchanges over a period of 2 weeks achieved healing of the lesions and resulted in the disappearance of pemphigus intercellular antibody from the serum. To our knowledge, only one case of penicillamine-induced pemphigus successfully treated with plasma exchange has been reported, though there exist reports of plasma exchange^1,2 used in the treatment of pemphigus vulgaris.     

Penile pemphigus

BACKGROUND: Penile skin involvement in patients with pemphigus vulgaris has been rarely reported. This study describes the involvement of penile skin in 12 patients with pemphigus vulgaris. OBSERVATIONS: Of the 12 patients, 10 had involvement of the skin and mucous membranes. Two patients had involvement of the oral mucosa only and no cutaneous involvement. None of the patients had urethral involvement. We did not observe isolated involvement of penile skin only, in the absence of disease elsewhere. Using monkey esophagus as substrate, all the patients had detectable levels of antibodies to keratinocyte cell surface antigen(s) in their serum samples. Since histological, serological, and clinical evidence of pemphigus was present, biopsies of the penile skin were not done. Topical therapy was concomitantly used with systemic therapy. Once treated and resolved, recurrence of penile lesions was not observed during the long-term follow-up. CONCLUSIONS: Involvement of penile skin is rare and was observed with the presence of pemphigus lesions in other areas of the body. Lesions involving the penile skin were most commonly seen on the glans. No sequelae or functional abnormalities were observed on long-term follow-up.     

Penicillamine-induced elastosis perforans serpiginosa. Tip of the iceberg?

Elastosis perforans serpiginosa (EPS) is now a well-recognized potential complication of long-term penicillamine therapy. By itself, EPS appears to be a relatively innocuous cutaneous side effect of penicillamine. However, suspicion has been raised in recent literature that EPS may represent only a superficial manifestation of more serious penicillamine-induced systemic elastic tissue damage, particularly involving blood vessels. This is a report of a patient with Wilson's disease who was treated with penicillamine for 14 years. She developed EPS, and histologic examination of the skin revealed the characteristic penicillamine-induced "lumpy-bumpy" elastic fibers in the dermis. More important, nonlesional skin showed the same elastic fiber changes. Of greatest significance was the finding of identical elastic fiber alterations in an artery.     

Penicillamine Revisited: Historic Overview and Review of the Clinical Uses and Cutaneous Adverse Effects

Penicillamine is a well-known heavy metal chelator, classically used in the treatment of Wilson disease, rheumatoid arthritis, and cystinuria. From a dermatologic standpoint, penicillamine was found to be useful in the treatment of systemic sclerosis. The successful therapeutic uses of penicillamine have been hindered by its numerous adverse effects, both cutaneous and extra-cutaneous. It is a unique drug since it provokes a diversity of dermatologic manifestations that include (1) acute hypersensitivity reactions, (2) dermopathies characterized by elastic fiber abnormalities including elastosis perforans serpiginosa and pseudo-pseudoxanthoma elasticum, (3) autoimmune disorders such as pemphigus and penicillamine-induced lupus erythematosus-like syndrome, and (4) miscellaneous dermatoses that result from undefined mechanisms. These cutaneous adverse effects may correlate with the dosage and duration of penicillamine therapy as well as the disease being treated.     

SIGNIFICANCE OF IN VIVO-BOUND IMMUNOGLOBULINS AND COMPLEMENT IN THE SKIN OF SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS

A direct immunofluorescent test was used to demonstrate the in vivo deposits of immunoglobulin (Ig) and complement in the skin of 30 patients with systemic lupus erythematosus (SLE). These deposits were demonstrated in all skin lesions and in 70% of apparently normal skin of patients with lupus nephritis. On the contrary, they were seldom found in seemingly normal skin of patients without nephritis, though they could be seen in skin lesions. There was significant difference between these two groups and as well as an intimate relation of the deposits to clinical severity. The fixed Ig and/or complement could be found in a band arrangement in the basement membrane zone (BMZ) area, nuclear areas of epidermal and/or dermal cells or both BMZ area and nuclear areas.     

Skin lesions in acquired zinc deficiency due to parenteral nutrition.

The skin lesions seen in 10 patients who received parenteral nutrition during treatment of chronic enteropathy are described. All of these patients had a lowered serum zinc concentration. The skin lesions were similar to those seen in acrodermatitis enteropathica. After supplementation with zinc sulphate, the skin lesions disappeared completely. A decrease in the serum alkaline phosphatase level can be regarded as a sign of an impending zinc deficiency. Parenteral nutrition formulae should contain a sufficient amount of zinc.     

Penicillamine induced pseudoxanthoma elasticum with elastosis perforans serpiginosa

Long term D-penicillamine therapy, especially when used to treat Wilson's disease has been shown to cause elastosis perforans serpiginosa, pseudoxanthoma elasticum perforans and other degenerative dermatoses. We report a 23-year-old male patient who presented with multiple firm papules, nodules over the neck, axillae, front of elbows for five years. He was a known case of Wilson's disease on long-term treatment with penicillamine for the past 12 years. The papulonodular lesions were non-tender and some were discrete while others were arranged in a circinate pattern. There was central scarring of the skin within the circinate lesions. In addition, there were several small yellowish papules on both sides of the neck which eventually became confluent to form plaques. Histopathology confirmed the diagnosis of elastosis perforans serpiginosa and pseudoxanthoma elasticum. He was treated with cryotherapy (using liquid nitrogen through cryojet) for former lesions. The lesions showed remarkable improvement after five sittings. Now the patient is under trientine hydrochloride (750 mg twice daily) for Wilson's disease.