Scleroderma and Penicillamine

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Rapid Progression of Scleroderma Possibly Associated with Penicillamine TherapyAuthor: Yosef S. Haviv, Rifaat Safadi, Division of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel [Clin Drug Invest 15(1):61-63, 1998. © 1998 Adis International Limited]

IntroductionSystemic sclerosis is a disorder affecting the skin and internal organs. Its pathogenesis consists of fibrosis and vasculopathy, secondary to inflammation and immunological dysregulation. The latter may involve increased macrophage synthesis of interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF), leading to proliferation of fibroblasts and endothelial cells. The pathogenesis is probably mainly influenced by environmental factors rather than genetic factors.[1] However, chemical-associated systemic sclerosis has been linked to human leucocyte antigen (HLA)-type, chromosomal abnormalities, and enzyme deficiencies.[2] Importantly, chemical-associated systemic sclerosis cannot be distinguished pathologically or clinically from idiopathic systemic sclerosis. Scleroderma-like skin changes have been associated with several occupational compounds. Internal organs are usually not involved in these disorders. The classic syndrome is the well known toxic oil syndrome that affected 20 000 people in Spain. In this epidemic, 10% of affected people developed a chronic scleroderma-like disorder, with a positive antinuclear factor. Many of them also had HLA-DR3 and DR4. Other well characterised chemicals associated with scleroderma are solvents such as chlorinated, aliphatic and aromatic hydrocarbons, silica, plastic materials such as epoxy resins and vinyl chloride, detergent, herbicides, silicone prostheses, and various drugs, among which are bleomycin, amphetamine, cocaine, amfepramone (diethylpropion), pentazocine, and penicillamine.[3] In this paper, we describe a patient who presented with scleroderma and while treated with penicillamine and high-dose corticosteroids, developed rapidly progressive systemic sclerosis and normotensive scleroderma renal crisis.

Case ReportA 58-year-old Caucasian male had hypothyroidism for 20 years, following Hashimoto's thyroiditis. At the age of 50 years, he presented with weight loss and lymphadenopathy; Hodgkin's disease, mixed cellularity type, stage 3B, was diagnosed. He was treated with chemotherapy [adriamycin, bleomycin, vinblastine (ABV) and cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone (CHOP)] for 6 months, and complete remission was achieved. Eight years later the patient presented with malaise, dysphagia, dyspnoea, night sweats and an 8kg weight loss within the last 3 months, and sclerodactyly and Raynaud's phenomenon for the last 3 weeks. On physical examination he was anicteric, afebrile and had a supine blood pressure of 110/80mm Hg. Sclerodactyly and telangiectasis were the only evidence of skin involvement. Laboratory data disclosed a Westergren erythrocyte sedimentation rate of 80 mm/first hour, and normocytic normochromic anaemia of 10 g/dl. Urinalysis was normal. Serum electrolytes, renal and liver function tests, including LDH and bilirubin, were all normal. A serological study revealed strongly positive antinuclear antibody (ANA) and antitopoisomerase I antibody (formerly anti SCL-70 antibody), but normal C3, anti-DNA, anti-centromere, anti-ribonucleoprotein (RNP), anti-Ro and anti-La antibodies. No paraprotein was found in the blood or urine. Chest x-ray and CT scan showed bilateral basilar interstitial infiltrates. Trans-bronchial biopsy showed interstitial fibrosis (fig. 1) compatible with systemic sclerosis, without evidence of malignancy or infection.

Figure 1. (click image to zoom) Trans-bronchial biopsy showing interstitial fibrosis compatible with systemic sclerosis, without evidence of malignancy or infection.

Bone marrow aspiration and biopsy were normal, except for erythroid hyperplasia. The patient was diagnosed clinically as having systemic sclerosis, involving the lung but without renal vascular disease. There was no evidence of relapse of the Hodgkin's disease. The patient was treated with penicillamine 250 mg/day and prednisone 60 mg/day. However, he displayed rapidly progressive skin thickening, spreading from the hands centripetally to the trunk in a few weeks. Therapy was not altered during that period and the blood pressure remained normal. Urine was not tested during this period. Four months later the patient presented with acute renal failure and anaemia of 5 g/dl. Mental status and temperature were normal, and the blood pressure was 108/72mm Hg. A blood smear disclosed schistocytes, reticulocytes and thrombocytopenia of 65 000/µl. The total bilirubin was 34 µmol/L with undetectable direct bilirubin,LDH 850 IU/L, blood urea 22 mmol/L, and blood creatinine 212 µmol/L. Proteinuria, haematuria and granular casts were found on urinalysis. Activated partial thromboplastin time, prothrombin time, fibrinogen and liver enzymes were normal. The clinical picture was compatible with haemolytic uraemic syndrome, secondary to systemic sclerosis, and necessitated acute peritoneal dialysis and plasmapheresis. Microangiopathic haemoytic changes resolved within a month, but the severe renal failure persisted. Unfortunately, the patient eventually succumbed to fulminant sepsis, 6 months after the initial cutaneous manifestations.

DiscussionPenicillamine is a heavy metal chelator used for the treatment of 's disease, rheumatoid arthritis, primary biliary cirrhosis, heavy metal poisoning and cystinuria. It is used occasionally for scleroderma, but its efficiency is controversial.[4,5] Penicillamine may induce several autoimmune disorders, such as systemic lupus erythematosus, membranous nephropathy, polymyositis, myasthenia gravis and pemphigus. In these diseases, abnormal immunoregulation is probably the main pathophysiology, perhaps involving dysregulation of T-lymphocytes and deposition of immune-complexes at the dermal-epidermal junction.[6,7] However, pemphigus is not the only adverse dermatological effect of penicillamine, as lichen planus,[8] elastosis perforans serpinginosa,[9] cutis laxa and pseudoxanthoma elasticum,[10] have also been associated with prolonged high-dose administration of penicillamine. In the latter cases, histology usually reveals irregular thickening of the elastic fibres of the dermis, with bleb-like protrusions perpendicular to their long axes. Similar changes associated with penicillamine have also been described in other tissues, such as the upper respiratory tract,[11] lungs,[12] joints[13] and aorta.[10] The mechanism is postulated to be maturation arrest and destabilisation of collagen and elastin, by interference with their cross-linking.[11] These histological findings are not usually found in scleroderma,[6] but penicillamine may induce various related connective tissue disorders, such as morphea,[14] systemic sclerosis,[6] vasculitis in rheumatoid arthritis,[15] and dermatomyositis and polymyositis, often associated with antinuclear antibodies and B8, DR-3 HLA-B8, DR3,[16,17] and transiently positive anti Jo-1 antibodies.[18] Penicillamine is probably not significantly effective in systemic sclerosis, except for mild lung function improvement.[4] This case raises the possibility that penicillamine may even be harmful in certain patients, and may perhaps be associated with acceleration of the decline in the course of the disease. The mechanism may involve either immune dysregulation or the generation of free radicals, directly toxic to the endothelium and leading to fibrotic tissue repair and intimal thickening.[3] Correspondence and reprints: Dr Yosef S. Haviv, Division of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, P.O.B 12000, Israel. E-mail: havivyo@...

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