Dermatologica 152: 358-362 (1976)
Pemphigus Vulgaris Following o-Penicillamine Ellis F rom and Poul F rederiksen Department of Dermatology and Venereology, Marselisborg Hospital, and the Institute of Pathology, Aarhus Municipal Hospital, University of Aarhus, Aarhus
Key Words. D-Penicillamine • Pemphigus vulgaris ■Systemic sclerosis Abstract. A 54-year-old woman with systemic sclerosis developed clinical, histo pathologic and immunopathologie findings consistent with pemphigus vulgaris after 8 months treatment with D-pcnicillamine. The course of the bullous disease required sustained steroid treatment.
Penicillamine which is dimethylcysteine is an effective agent in Wilson’s disease. Within recent years, this drug has also been used in severe rheuma toid arthritis, systemic sclerosis and a number of other conditions. Although D-penicillamine is reckoned to be less toxic than the l or dl forms [11], side effects are not uncommon. Fever, rashes, leucopenia, eosinophilia and thrombocytopenia have been encountered, and loss of taste, a nephrotic syndrome, a lupus-like syndrome, polymyositis and pemphigus have also been reported [1, 4, 5, 6, 8, 12, 13]. This report describes a patient whose pemphigus vulgaris was presumably caused by D-penicillamine taken for systemic sclerosis. Case Report
Received: March 3, 1976; accepted: March 29, 1976.
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The patient, a 54-year-old woman, attended our hospital for the first time in January 1975 having had symptoms of Raynaud's phenomenon for 2 years together with typical scleroderma of distal parts of the extremities and of her face and neck. A lung function test
F rom/Frederiksen
359
Fig. I. Bullous lesions arising from apparently normal skin together with excoriations.
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revealed slight involvement of the lungs, while no roentgenologic changes of oesophagus were detected. Histology of the skin showed scleroderma The patient was treated with o-pcnicillamine (Dimethylcysteine® Dista) 300 mg three times daily. She also received betamethasone (Celeston®) 0.5 mg three times daily and furosemide (Nicorol®) 40 mg daily. Pyridoxine was given 20 mg three times daily as dietary supplementation. Having received penicillamine for 8 months, she suddenly developed a bullous eruption with tense and flaccid bullae of varying size on her trunk, arms and legs (fig I) arising on apparently normal skin. Bullae also appeared upon the oral mucosa. The blister spreading phenomenon was positive. Clinically, pemphigus or pem phigoid was suggested, but in the light microscope, changes compatible with pemphigus were found, viz., intraepidermal bullae and acantholytic cells (fig. 2). Penicillamine was withheld and betamethasone increased to 2 mg three times a day. The patient continued to receive furosemide. In the following weeks many new bullae arised, but after 5 weeks the bulla formation ceased and the denuded areas of the skin started to heal.
360
F rom/Frederiksen
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Fig. 2. Punch biopsy from margin of bullous lesion showing intraepidermal bulla and severe acantholysis. Fig. 3. Direct immunofluorescence investigation of normal skin close to lesion showing intercellular-bound IgG in a net-like pattern.
Pemphigus Vulgaris Following D-Penicillamine
361
Routine laboratory investigations of the blood gave normal results, albuminuria was not detected. The antinuclear factor was strongly positive, LE cells negative. Antimitochondrial and antiparictal antibodies could not be detected. Antistriated muscle antibodies were present in an insignificant titre. The scrum levels of aldolase and creatinkinase were not increased. Serum IgF. was normal. An X ray of the chest showed no evidence of thy moma. Tissue typing showed HL-AI3. Immunofluorescence studies were performed with commercially available fluoresceinisothiocyanat (F1TC) conjugated rabbit-antihuman y-globulin G, M, A and anticomple ment (fj, C/J3, A) (Behringwerke). Protein content 10 mg/ml. Molar F/P ratio 2.0. Working dilution 1:4. Normal human skin, human and monkey oral mucosa served as substrate in the indirect technique. The patients serum was investigated in dilution 1:10, 1:40 and 1:100. The readings were made with a Zeiss microscope with a HB200 W mercury lamp. F1TC inter ference filter was used as primary filter, and filter type No. 50 as secondary filter.
Results In the direct immunofluorescence study, IgG and complement intercellular staining was found in the epidermis (fig. 3) in a net like pattern typical for pemphigus. Similar investigations performed prior to penicillamine treat ment revealed no such deposits. Repeated examination of the patients serum for circulating intercellular antibodies was negative.
Comments
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The diagnosis of pemphigus vulgaris was established in our patient suffering from systemic sclerosis by the clinical features in combination with biopsy evidence of an intraepidermal bulla with acantholytic cells and speci fic fluorescence in the intercellular substance of the epidermis. That indirect immunofluorescence staining for pemphigus antibodies was negative may be due to an interference phenomenon produced by the antinuclear factor. Another reason could be a limited species and organ specificity of the pem phigus antibody or that the antibodies could be absorbed from plasma by the epidermis [2, 3], Pemphigus after penicillamine therapy has been reported by D egos et al. [4] in a young man with Wilson's disease treated for a long time with openicillamine. The pemphigus antibody titre was low. Nine cases of pem phigus induced by D-penicillamine given for rheumatoid arthritis have also been observed [6-8]. The pemphigus was most commonly of the foliaceus type. Antibodies were present in all nine cases, but were usually of low titre.
362
F rom/Frederiksen
After stopping treatment with penicillamine some were easily cured, while others ran the more classical course of the disease and required steroid treatment. A case of pemphigus foliaceus in systemic sclerosis treated with penicillamine has been reported by A sbol-H ansen [1]. How penicillamine can induce pemphigus is unknown. Perhaps the drug may bind to epidermal proteins and act as a hapten [10]. Tissue typing showed that our patient had HL-A13. According to K atz et aL [9] this tissue antigen reveals a greater susceptibility to develop pemphigus.
References 1 A sboe-FIansen, G. : Treatment of generalized scleroderma with inhibitors of connective tissue formation. Acta derm.-verier., Stockh. 55: 461-465 (1975). 2 C horzelski, T.; J ablonska, S.; Blaszczyk , M. und J arzabek, M.: Wert dcr Autoantikorperbestimmung beim Pemphigus. Hautarzt IS: 521-524(1967). 3 C horzelski, T.P. and Beutner, E.H.: Factors contributing to occasional failures in demonstration of pemphigus antibodies by the immunofluorescence test. J. invest. Derm. 53: 188-191 (1969). 4 D egos, M .M .R.; T ouraine , R.; Belaich, S. et R evuz, J.: Pemphigus chez un malade traité par penicillamine pour maladie de Wilson. Bull. Soc. fr. Derm. Syph. 76:751-753 (1969). 5 FIarpey, J.P.; C aille, B.; M oulias, R., and G oust, J.M.: Lupus-like syndrome induced by D-penicillamine in Wilson's disease. Lancet i: 292 (1971 ). 6 H ewitt , J.; L essana-L eibowjtch, M.; Benveniste, M. et S aporta, L.: Un cas de pemphigus induit par la D-penicillamine. Annls Med. intern. 122: 1003-1009 (1971). 7 H ewitt, J.: Annu. Meet. British Association of Dermatologists, Cambridge, 1975. 8 H ewitt , J.; Benveniste, M., and L essana-L eibowitch, M.: Pemphigus induced by D-penicillamine. An ‘experimental’ pemphigus. Br. J. Derm. 93: suppl. 12 (1975). 9 K atz , S.I.; D ahl, M .V .; P enneys, N .; T rapani, R.J., and R ogentine , N .: HL-A Antigens in pemphigus. Archs Derm. 108: 53-55 (1973). 10 L evine, B.B.: Formation of D-penicillamine cysteine mixed disulphide by reaction of D-benzylpenicilloic acid with cystine. Nature, Lond. 187: 940 (1960). 11 L evine, W .G .: Heavy metal antagonists; in G oodman and G ilman Pharmacological basis of therapeutics (Mac-Millan, New York 1971). 12 N ishikai, M.; F unatsu, Y., and H omma, M.: Monoclonal gammopathy penicillamineinduced polymyositis and systemic sclerosis. Archs Derm. 110: 253-255 (1974). 13 P ass, F.; G oldfischer, S.; Sternlieb, 1. and Scheinberg, I.H.: Elastosis perforans serpiginosa during penicillamine therapy for Wilson's disease. Archs Derm. 108: 713715 (1973).
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E llis F rom, MD, Department of Dermatology, Marselisborg Hospital, University of Aarhus, 8000 Aarhus C (Denmark)
Pemphigus Vulgaris Following o-Penicillamine Ellis F rom and Poul F rederiksen Department of Dermatology and Venereology, Marselisborg Hospital, and the Institute of Pathology, Aarhus Municipal Hospital, University of Aarhus, Aarhus
Key Words. D-Penicillamine • Pemphigus vulgaris ■Systemic sclerosis Abstract. A 54-year-old woman with systemic sclerosis developed clinical, histo pathologic and immunopathologie findings consistent with pemphigus vulgaris after 8 months treatment with D-pcnicillamine. The course of the bullous disease required sustained steroid treatment.
Penicillamine which is dimethylcysteine is an effective agent in Wilson’s disease. Within recent years, this drug has also been used in severe rheuma toid arthritis, systemic sclerosis and a number of other conditions. Although D-penicillamine is reckoned to be less toxic than the l or dl forms [11], side effects are not uncommon. Fever, rashes, leucopenia, eosinophilia and thrombocytopenia have been encountered, and loss of taste, a nephrotic syndrome, a lupus-like syndrome, polymyositis and pemphigus have also been reported [1, 4, 5, 6, 8, 12, 13]. This report describes a patient whose pemphigus vulgaris was presumably caused by D-penicillamine taken for systemic sclerosis. Case Report
Received: March 3, 1976; accepted: March 29, 1976.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:06:08 AM
The patient, a 54-year-old woman, attended our hospital for the first time in January 1975 having had symptoms of Raynaud's phenomenon for 2 years together with typical scleroderma of distal parts of the extremities and of her face and neck. A lung function test
F rom/Frederiksen
359
Fig. I. Bullous lesions arising from apparently normal skin together with excoriations.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:06:08 AM
revealed slight involvement of the lungs, while no roentgenologic changes of oesophagus were detected. Histology of the skin showed scleroderma The patient was treated with o-pcnicillamine (Dimethylcysteine® Dista) 300 mg three times daily. She also received betamethasone (Celeston®) 0.5 mg three times daily and furosemide (Nicorol®) 40 mg daily. Pyridoxine was given 20 mg three times daily as dietary supplementation. Having received penicillamine for 8 months, she suddenly developed a bullous eruption with tense and flaccid bullae of varying size on her trunk, arms and legs (fig I) arising on apparently normal skin. Bullae also appeared upon the oral mucosa. The blister spreading phenomenon was positive. Clinically, pemphigus or pem phigoid was suggested, but in the light microscope, changes compatible with pemphigus were found, viz., intraepidermal bullae and acantholytic cells (fig. 2). Penicillamine was withheld and betamethasone increased to 2 mg three times a day. The patient continued to receive furosemide. In the following weeks many new bullae arised, but after 5 weeks the bulla formation ceased and the denuded areas of the skin started to heal.
360
F rom/Frederiksen
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:06:08 AM
Fig. 2. Punch biopsy from margin of bullous lesion showing intraepidermal bulla and severe acantholysis. Fig. 3. Direct immunofluorescence investigation of normal skin close to lesion showing intercellular-bound IgG in a net-like pattern.
Pemphigus Vulgaris Following D-Penicillamine
361
Routine laboratory investigations of the blood gave normal results, albuminuria was not detected. The antinuclear factor was strongly positive, LE cells negative. Antimitochondrial and antiparictal antibodies could not be detected. Antistriated muscle antibodies were present in an insignificant titre. The scrum levels of aldolase and creatinkinase were not increased. Serum IgF. was normal. An X ray of the chest showed no evidence of thy moma. Tissue typing showed HL-AI3. Immunofluorescence studies were performed with commercially available fluoresceinisothiocyanat (F1TC) conjugated rabbit-antihuman y-globulin G, M, A and anticomple ment (fj, C/J3, A) (Behringwerke). Protein content 10 mg/ml. Molar F/P ratio 2.0. Working dilution 1:4. Normal human skin, human and monkey oral mucosa served as substrate in the indirect technique. The patients serum was investigated in dilution 1:10, 1:40 and 1:100. The readings were made with a Zeiss microscope with a HB200 W mercury lamp. F1TC inter ference filter was used as primary filter, and filter type No. 50 as secondary filter.
Results In the direct immunofluorescence study, IgG and complement intercellular staining was found in the epidermis (fig. 3) in a net like pattern typical for pemphigus. Similar investigations performed prior to penicillamine treat ment revealed no such deposits. Repeated examination of the patients serum for circulating intercellular antibodies was negative.
Comments
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 9:06:08 AM
The diagnosis of pemphigus vulgaris was established in our patient suffering from systemic sclerosis by the clinical features in combination with biopsy evidence of an intraepidermal bulla with acantholytic cells and speci fic fluorescence in the intercellular substance of the epidermis. That indirect immunofluorescence staining for pemphigus antibodies was negative may be due to an interference phenomenon produced by the antinuclear factor. Another reason could be a limited species and organ specificity of the pem phigus antibody or that the antibodies could be absorbed from plasma by the epidermis [2, 3], Pemphigus after penicillamine therapy has been reported by D egos et al. [4] in a young man with Wilson's disease treated for a long time with openicillamine. The pemphigus antibody titre was low. Nine cases of pem phigus induced by D-penicillamine given for rheumatoid arthritis have also been observed [6-8]. The pemphigus was most commonly of the foliaceus type. Antibodies were present in all nine cases, but were usually of low titre.
362
F rom/Frederiksen
After stopping treatment with penicillamine some were easily cured, while others ran the more classical course of the disease and required steroid treatment. A case of pemphigus foliaceus in systemic sclerosis treated with penicillamine has been reported by A sbol-H ansen [1]. How penicillamine can induce pemphigus is unknown. Perhaps the drug may bind to epidermal proteins and act as a hapten [10]. Tissue typing showed that our patient had HL-A13. According to K atz et aL [9] this tissue antigen reveals a greater susceptibility to develop pemphigus.
References 1 A sboe-FIansen, G. : Treatment of generalized scleroderma with inhibitors of connective tissue formation. Acta derm.-verier., Stockh. 55: 461-465 (1975). 2 C horzelski, T.; J ablonska, S.; Blaszczyk , M. und J arzabek, M.: Wert dcr Autoantikorperbestimmung beim Pemphigus. Hautarzt IS: 521-524(1967). 3 C horzelski, T.P. and Beutner, E.H.: Factors contributing to occasional failures in demonstration of pemphigus antibodies by the immunofluorescence test. J. invest. Derm. 53: 188-191 (1969). 4 D egos, M .M .R.; T ouraine , R.; Belaich, S. et R evuz, J.: Pemphigus chez un malade traité par penicillamine pour maladie de Wilson. Bull. Soc. fr. Derm. Syph. 76:751-753 (1969). 5 FIarpey, J.P.; C aille, B.; M oulias, R., and G oust, J.M.: Lupus-like syndrome induced by D-penicillamine in Wilson's disease. Lancet i: 292 (1971 ). 6 H ewitt , J.; L essana-L eibowjtch, M.; Benveniste, M. et S aporta, L.: Un cas de pemphigus induit par la D-penicillamine. Annls Med. intern. 122: 1003-1009 (1971). 7 H ewitt, J.: Annu. Meet. British Association of Dermatologists, Cambridge, 1975. 8 H ewitt , J.; Benveniste, M., and L essana-L eibowitch, M.: Pemphigus induced by D-penicillamine. An ‘experimental’ pemphigus. Br. J. Derm. 93: suppl. 12 (1975). 9 K atz , S.I.; D ahl, M .V .; P enneys, N .; T rapani, R.J., and R ogentine , N .: HL-A Antigens in pemphigus. Archs Derm. 108: 53-55 (1973). 10 L evine, B.B.: Formation of D-penicillamine cysteine mixed disulphide by reaction of D-benzylpenicilloic acid with cystine. Nature, Lond. 187: 940 (1960). 11 L evine, W .G .: Heavy metal antagonists; in G oodman and G ilman Pharmacological basis of therapeutics (Mac-Millan, New York 1971). 12 N ishikai, M.; F unatsu, Y., and H omma, M.: Monoclonal gammopathy penicillamineinduced polymyositis and systemic sclerosis. Archs Derm. 110: 253-255 (1974). 13 P ass, F.; G oldfischer, S.; Sternlieb, 1. and Scheinberg, I.H.: Elastosis perforans serpiginosa during penicillamine therapy for Wilson's disease. Archs Derm. 108: 713715 (1973).
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E llis F rom, MD, Department of Dermatology, Marselisborg Hospital, University of Aarhus, 8000 Aarhus C (Denmark)
