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Metal antagonists
R.H.B. Meyboom and I.A. Jaffe
24
Metal antagonists
Penicillamine (SED-1 O, 409; SEDA-8, 235)
as compared with only 1 of the remaining 14 patients with extensive sulfoxidation capacity.
In the past 20 years penicillamine has attracted much attention and its side effects have been the subject of an avalanche of publications. In the period covered by this Annual, little new has been added to our knowledge of this intriguing drug, and the flow of work has declined. Ahern et al (1 c ) have studied the effects on rheumatoid arthritis of gradual withdrawal of penicillamine. In their series 80% of the patients subsequently experienced a relapse! Penieillamine and gold, again As pointed out in previous volumes, there are many similarities between penicillamine and gold as regards their effect on rheumatoid arthritis and their adverse reactions. The possible consequences with respect to cross-intolerance and the prevention of adverse reactions were reviewed in SEDA-8 (p. 236). Interest in this issue has been renewed by the interesting case observation of Moore et al ( 2 c ) . These authors describe a patient with typical penicillamine-induced myasthenia, subsiding after stopping the drug. Interestingly, she suffered from a second attack of myasthenia when receiving injections of sodium aurothiomalate, again recovering after withdrawal o f the gold treatment. Risk factors As has been suggested by Panayi et al (3c), a patient's sulfoxidation capacity may be of importance with respect to the development of adverse reactions to penicillamine. In their preliminary series of 20 patients on penicillarnine, 5 of 6 poor sulfoxidizers experienced adverse reactions,
Side Effects of Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page (transactional system) $0.20 per article per page (licensing system)
Skin and appendages The pluriform skin reactions to penicillamine have recently been reviewed by Levy et al (4R). A further case, well-documented, has been reported of penicillamine-associated dermatomyositis (5CR). Originally discovered in France, penicillamine-induced pemphigus has on the basis of three new and severe cases been thoroughly reviewed by Verret et al (6CR). The case reported by Dofitre et al ( 7 c ) , again of the pemphigus erythematosus type, even had a fatal outcome. In many (but not all) published cases, antibodies to intercellular substance have been demonstrated. Presumably the disorder has to endure for some time before these pemphigus antibodies appear in the blood
(6). PeniciUamine and the yellow nail syndrome In 1967, a 9-year-old girl with Wilson's disease was described in whom, during long-term use o f penicillamine in a dose o f 1 g daily, onychopathy developed together with stomatitis and glossitis (8). The nail disorder consisted o f deep longitudinal ridges with leukonychia and crumbling o f the nails; it disappeared on stopping and recurred after resuming the administration o f penicillamine. In their rheumatic patient with yellowishgreen discolored, thickened and friable nails, paronychia and respiratory tract infections, a condition which recovered after stopping penicillamine, Lubach and Marghescu were the first to recognize the resemblance to the yellow nail syndrome (SEDA5, 248). Recently, another patient with the yellow nail syndrome has been described (9). This
224
patient, while on 750 mg penicillamine for rheumatoid arthritis, developed thickening, ridging and yellow discoloration o f the nails o f fingers and toes. The nails also appeared to have retarded growth. Some 9 months after stopping penicillamine the appearance o f the nails returned to normal. A review o f the genuine yellow nail syndrome is given by Leiber and Olbrich (I OR J. The syndrome is associated with pleural effusions and bronchitic s y m p t o m s and develops secondary to (congenital} lymphedema. Blood The fourth case has now been reported of thrombotic thrombocytopenic purpura (Moschcowitz's syndrome), attributed to the use of penicillamine ( l l C R ) . Although the 3 previous cases of this syndrome were all fatal (SED-10, 411), this fourth patient recovered on stopping penicillamine and receiving treatment with plasma exchange, prednisone and packed red blood cell transfusions. Musculoskeletal system In a series of 16 patients with penicillamine-induced myasthenia, Delamere et al (12 c) confirmed the increased occurrence o f the HLA-antigen Drl and the absence of Dr3 (which is otherwise frequept in myasthenia gravis), as has previously b l o t reported (SEDA-8,235). In addition to myasthenia gravis, polymyositis, dermatomyositis and neuromyotonia, diffuse fasciculations have now been
Chapter 24
R.H.B. Meyboom and LA. Jaffe
reported for the first time as a side effect of peniciUamine (13Cr). The patient in question experienced the development of constant and simultaneous fasciculations in the legs, arms and trunk, after 7 months of treatment with penicillamine for rheumatoid arthritis. Electromyography revealed spontaneous diffuse fasciculations in several muscle groups, although m o t o r unit action potentials had a normal configuration. The condition cleared soon after withdrawal of penicillamine and no other possible cause was found.
OTHER DRUGS
Deferoxamine (SED-9, 416; SEDA-8, 239) A further case has been reported of visual loss as a result of the use of very high doses of deferoxamine (15c). The patient, an 8year-old girl with /~-thalassemia, improved when deferoxamine was stopped.
Tiopronin (mercaptopropionylglycine) (SED-9, 41 7; SEDA-8, 240) The first case has been reported of the occurrence of pemphigus foliaceus in a patient on tiopronin for cystinuria (14c). This patient, who also developed proteinuria of 7 g/24 h, recovered after withdrawal o f the drug and 21A months of treatment with prednisone.
REFERENCES 1. Ahern MJ, Hall ND, Cade K, Maddison PJ (1984) D-Penicillamine withdrawal in rheumatoid arthritis. Ann. Rheum. Dis., 43, 213. 2. Moore AP, Williams AC, Hillenbrand P (1984) Penicillamine induced myasthenia reactivated by gold. Br. Med. J., 288, 192. 3. Panayi GS, Huston G, Shah RR et al (1983) Deficient sulphoxidation status and d-peniciUamine toxicity. Lancet, 1,414. 4. Levy RS, Fisher M, Alter JN (1983) Penicillamine: review and cutaneous manifestations. J. Am. Acad. DermatoL, 8, 548. 5. Lund HI, Nielsen M (1983) PeniciUamine-induced dermatomyositis. Scand. J. Rheumatol., 12, 350. 6. Verret JL, Avenel M, Smulevici A, Esparb~s M (1983) Les pemphigus induits ~ propos de trois cas. J. Agrbg~s, 16, 209. 7. Dofitre MS, Beylot C, Lassalle H et al (1983) Pemphigus eryth6mateux induit par la d-p6nicillamine. Rev. Rhum., 50, 167. 8. Thivolet J, Perrot H, Francois R (1967) Glossite, stomatite et onychopathie provoqu6es par la p6nicillamine. Bull. Soc. Fr. Dermatol., 74, 61.
9. Ilchyshyn A, Vickers CFH (1983) Yellow nail syndrome associated with penicillamine therapy. Acta Derm..Venereol., 63, 554. 10. Leiber B, Olbrich G (1981) Die klinische Syndrome, Band 1, p 1005. Urban & Schwarzenberg, Munich-Baltimore. 11. Trice JM, Pinals RS, Plitman GI (1983) Thrombotic thrombocytopenic purpura during penicillamine therapy in rheumatoid arthritis. Arch. Intern. Med., 143, 1487. 12. Delamere JP, Jobson S, Mackintosh LP et al (1983) Penicillamine-induced myasthenia in rheumatoid arthritis: its clinical and genetic features.Ann. Rheum. Dis., 42, 500. 13. Pinals RS (1983) Diffuse fasciculations induced by d-penicillamine. J. Rheumatol., 10, 809. 14. Lucky PA, Skovby F, Thier SO (1983) Pemphigus foliaceus and proteinuria induced by alpha-mercaptopropionylglycine. J. Am. A cad. Dermatol., 8, 667. 15. Borgna-Pignatti C, De Stefano P, Broglia AM (1984) Visual loss in patient on high-dose subcutaneous desferrioxamine. Lancet, 1, 681.
24
Metal antagonists
Penicillamine (SED-1 O, 409; SEDA-8, 235)
as compared with only 1 of the remaining 14 patients with extensive sulfoxidation capacity.
In the past 20 years penicillamine has attracted much attention and its side effects have been the subject of an avalanche of publications. In the period covered by this Annual, little new has been added to our knowledge of this intriguing drug, and the flow of work has declined. Ahern et al (1 c ) have studied the effects on rheumatoid arthritis of gradual withdrawal of penicillamine. In their series 80% of the patients subsequently experienced a relapse! Penieillamine and gold, again As pointed out in previous volumes, there are many similarities between penicillamine and gold as regards their effect on rheumatoid arthritis and their adverse reactions. The possible consequences with respect to cross-intolerance and the prevention of adverse reactions were reviewed in SEDA-8 (p. 236). Interest in this issue has been renewed by the interesting case observation of Moore et al ( 2 c ) . These authors describe a patient with typical penicillamine-induced myasthenia, subsiding after stopping the drug. Interestingly, she suffered from a second attack of myasthenia when receiving injections of sodium aurothiomalate, again recovering after withdrawal o f the gold treatment. Risk factors As has been suggested by Panayi et al (3c), a patient's sulfoxidation capacity may be of importance with respect to the development of adverse reactions to penicillamine. In their preliminary series of 20 patients on penicillarnine, 5 of 6 poor sulfoxidizers experienced adverse reactions,
Side Effects of Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page (transactional system) $0.20 per article per page (licensing system)
Skin and appendages The pluriform skin reactions to penicillamine have recently been reviewed by Levy et al (4R). A further case, well-documented, has been reported of penicillamine-associated dermatomyositis (5CR). Originally discovered in France, penicillamine-induced pemphigus has on the basis of three new and severe cases been thoroughly reviewed by Verret et al (6CR). The case reported by Dofitre et al ( 7 c ) , again of the pemphigus erythematosus type, even had a fatal outcome. In many (but not all) published cases, antibodies to intercellular substance have been demonstrated. Presumably the disorder has to endure for some time before these pemphigus antibodies appear in the blood
(6). PeniciUamine and the yellow nail syndrome In 1967, a 9-year-old girl with Wilson's disease was described in whom, during long-term use o f penicillamine in a dose o f 1 g daily, onychopathy developed together with stomatitis and glossitis (8). The nail disorder consisted o f deep longitudinal ridges with leukonychia and crumbling o f the nails; it disappeared on stopping and recurred after resuming the administration o f penicillamine. In their rheumatic patient with yellowishgreen discolored, thickened and friable nails, paronychia and respiratory tract infections, a condition which recovered after stopping penicillamine, Lubach and Marghescu were the first to recognize the resemblance to the yellow nail syndrome (SEDA5, 248). Recently, another patient with the yellow nail syndrome has been described (9). This
224
patient, while on 750 mg penicillamine for rheumatoid arthritis, developed thickening, ridging and yellow discoloration o f the nails o f fingers and toes. The nails also appeared to have retarded growth. Some 9 months after stopping penicillamine the appearance o f the nails returned to normal. A review o f the genuine yellow nail syndrome is given by Leiber and Olbrich (I OR J. The syndrome is associated with pleural effusions and bronchitic s y m p t o m s and develops secondary to (congenital} lymphedema. Blood The fourth case has now been reported of thrombotic thrombocytopenic purpura (Moschcowitz's syndrome), attributed to the use of penicillamine ( l l C R ) . Although the 3 previous cases of this syndrome were all fatal (SED-10, 411), this fourth patient recovered on stopping penicillamine and receiving treatment with plasma exchange, prednisone and packed red blood cell transfusions. Musculoskeletal system In a series of 16 patients with penicillamine-induced myasthenia, Delamere et al (12 c) confirmed the increased occurrence o f the HLA-antigen Drl and the absence of Dr3 (which is otherwise frequept in myasthenia gravis), as has previously b l o t reported (SEDA-8,235). In addition to myasthenia gravis, polymyositis, dermatomyositis and neuromyotonia, diffuse fasciculations have now been
Chapter 24
R.H.B. Meyboom and LA. Jaffe
reported for the first time as a side effect of peniciUamine (13Cr). The patient in question experienced the development of constant and simultaneous fasciculations in the legs, arms and trunk, after 7 months of treatment with penicillamine for rheumatoid arthritis. Electromyography revealed spontaneous diffuse fasciculations in several muscle groups, although m o t o r unit action potentials had a normal configuration. The condition cleared soon after withdrawal of penicillamine and no other possible cause was found.
OTHER DRUGS
Deferoxamine (SED-9, 416; SEDA-8, 239) A further case has been reported of visual loss as a result of the use of very high doses of deferoxamine (15c). The patient, an 8year-old girl with /~-thalassemia, improved when deferoxamine was stopped.
Tiopronin (mercaptopropionylglycine) (SED-9, 41 7; SEDA-8, 240) The first case has been reported of the occurrence of pemphigus foliaceus in a patient on tiopronin for cystinuria (14c). This patient, who also developed proteinuria of 7 g/24 h, recovered after withdrawal o f the drug and 21A months of treatment with prednisone.
REFERENCES 1. Ahern MJ, Hall ND, Cade K, Maddison PJ (1984) D-Penicillamine withdrawal in rheumatoid arthritis. Ann. Rheum. Dis., 43, 213. 2. Moore AP, Williams AC, Hillenbrand P (1984) Penicillamine induced myasthenia reactivated by gold. Br. Med. J., 288, 192. 3. Panayi GS, Huston G, Shah RR et al (1983) Deficient sulphoxidation status and d-peniciUamine toxicity. Lancet, 1,414. 4. Levy RS, Fisher M, Alter JN (1983) Penicillamine: review and cutaneous manifestations. J. Am. Acad. DermatoL, 8, 548. 5. Lund HI, Nielsen M (1983) PeniciUamine-induced dermatomyositis. Scand. J. Rheumatol., 12, 350. 6. Verret JL, Avenel M, Smulevici A, Esparb~s M (1983) Les pemphigus induits ~ propos de trois cas. J. Agrbg~s, 16, 209. 7. Dofitre MS, Beylot C, Lassalle H et al (1983) Pemphigus eryth6mateux induit par la d-p6nicillamine. Rev. Rhum., 50, 167. 8. Thivolet J, Perrot H, Francois R (1967) Glossite, stomatite et onychopathie provoqu6es par la p6nicillamine. Bull. Soc. Fr. Dermatol., 74, 61.
9. Ilchyshyn A, Vickers CFH (1983) Yellow nail syndrome associated with penicillamine therapy. Acta Derm..Venereol., 63, 554. 10. Leiber B, Olbrich G (1981) Die klinische Syndrome, Band 1, p 1005. Urban & Schwarzenberg, Munich-Baltimore. 11. Trice JM, Pinals RS, Plitman GI (1983) Thrombotic thrombocytopenic purpura during penicillamine therapy in rheumatoid arthritis. Arch. Intern. Med., 143, 1487. 12. Delamere JP, Jobson S, Mackintosh LP et al (1983) Penicillamine-induced myasthenia in rheumatoid arthritis: its clinical and genetic features.Ann. Rheum. Dis., 42, 500. 13. Pinals RS (1983) Diffuse fasciculations induced by d-penicillamine. J. Rheumatol., 10, 809. 14. Lucky PA, Skovby F, Thier SO (1983) Pemphigus foliaceus and proteinuria induced by alpha-mercaptopropionylglycine. J. Am. A cad. Dermatol., 8, 667. 15. Borgna-Pignatti C, De Stefano P, Broglia AM (1984) Visual loss in patient on high-dose subcutaneous desferrioxamine. Lancet, 1, 681.