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BRIEF REPORTS
Penicillamine-induced myasthenia gravis D-penicillamine has been established as an effective agent in the management of rheumatoid arthritis. It is also used to treat patients with Wilson’s disease and cystinuria. Myasthenia gravis has been reported to occur in patients receiving penicillamine treatment for both rheumatoid arthritis (1-3) and Wilson’s disease (43). This report describes two patients who developed myasthenia gravis while receiving penicillamine for the treatment of rheumatoid arthritis. CASE REPORT Patient 1. A 60-year-old white female developed bilateral polyarthropathy involving the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrists, knees, ankles, and inetatarsophalangeal (MTP) joints. Extraarticular manifestations included fatigue, bilateral carpal tunnel syndrome, and Raynaud’s phenomenon. American Rheumatism Association functional class progressed from Class I to Class 3 between 1970 and 1976. Therapy with salicylates and nonsteroidal drugs was unsuccessful in controlling her disease. A trial of gold sodium thiomalate was complicated by oral ulcerations and generalized skin rash after a total dose of 650 mg, thus necessitating withdrawal of gold. Penicillamine (250 mg/day)’was begun in 1976 and gradually increased to 750 mg/day. Within 5 months, the functional class had improved from Class 3 to Class 1. Seven months after the initiation of therapy, unilateral ptosis, generalized muscular weakness, and masseter fatigue were noted. Within 1 month, she was unable to chew solid food and could not forcibly close her jaws after chewing for 2 to 5 minutes. Physical examination revealed ptosis of the right palpebral fissure, slight indistinct speech, and fatigue of masseter function following gum chewing. A test dose of normal saline produced no improvement. Edrophonium sulfate, 4 mg intravenously, was followed by a loss of ptosis and masseter fatigue. Electromyography was not done. Penicillamine was discontinued; anticholinesterase drugs were not administered. The symptoms of myasthenia improved over 8 weeks and have not recurred. Currently, the rheumatoid disease is managed with fenoprofen, 1800 mg/day, and prednisone, 2.5 mg/day. Patient 2. A 54-year-old male with a 30 year history of rheumatoid arthritis characterized by symmetrical polyarthropathy and joint deformity was placed on penicillamine therapy following failure with the following regimes: aspirin, nonsteroidal drugs, gold, and low dose steroids. The dose of penicillamine was gradually increased to 1.5 gm/day. This was followed by an increase in myalgias, dysgeusia, nausea, and diarrhea. Reduction of penicillamine to 750 mg was folArthritis and Rheumatism, Val. 22, No. 2 (February 1979)
lowed by cessation of these symptoms. Improvement of the rheumatoid arthritis, both subjective and objective, was noted at this time. Within 6 months (10 months following the initiation of penicillamine treatment), the patient complained of diplopia and blurred vision. Examination revealed a left third nerve paresis and bilateral ptosis, and a tensilon test confirmed the impression of myasthenia gravis. Following intravenous edrophonium, the patient’s ptosis and abnormalities of extraocular motion disappeared. Electromyography revealed a characteristic response to tetanic stimulation. Anticholinesterase medications (pyridostigmine and neostigmine) were begun, penicillamine was discontinued, and the myasthenia improved. During the subsequent clinical course, myasthenia crisis was precipitated by a flu syndrome and the patient required assisted ventilation and hospitalization. Penicillamine was resumed when the underlying arthropathy worsened 2 months later. The drug was discontinued permanently following the first published report of penicillamine associated with the myasthenia syndrome. There was a gradual improvement manifested by clearing of ptosis, third nerve paresis, difficulty in swallowing, and weakness of the neck extensors. The patient has been off penicillamine for 26 months and continues on 540 mg of pyridostigmine and 60 mg of neostigmine daily.
DISCUSSION The occurrence of myasthenia gravis in association with rheumatoid arthritis appears to be rare, although it is difficult to document. Our experience reveals only one case of idiopathic myasthenia gravis in 400 cases of rheumatoid arthritis (0.25%). Others have demonstrated an increase in the frequency of rheumatoid arthritis in myasthenia gravis (1). However, it is felt that this is related to the “two disease fallacy” concept, i.e., patients with two diseases are more likely to be admitted to a hospital, to attract attention, and to be mentioned in the literature. The infrequency of rheumatoid arthritis associated with myasthenia suggests that it occurs by chance and not as an associated immunologic phenomenon. The recent observation that reversible myasthenia gravis apparently occurs more frequently in rheumatoid arthritis patients receiving penicillamine suggests that penicillamine is a causal factor. The relationship of clinical syndromes indistinguishable from systemic lupus erythematosus (6), Goodpasture’s syndrome (7), and polymyositis (8,9) in patients receiving penicillamine further implicates the ability of penicillamine to induce or unmask abnormalities of immune function. Recently, Masters (4) studied 56 patients receiving penicillamine for rheumatoid arthritis. None of the patients had overt myasthenia gravis. Two complained
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of fatigue and had evidence on electromyography of defective neuromuscular function. Anti-striational antibodies were found in the sera of 11 patients, one of whom had a significantly elevated anti-skeletal muscle antibody and a slight increase in acetylcholine receptor antibody. In addition, Masters studied the sera of 5 patients who developed clinical myasthenia gravis while undergoing penicillamine treatment for rheumatoid arthritis. Anti-acetylcholine receptor antibodies were present in 4 of these 5 patients (5). These antibodies are implicated as a pathogenic factor in myasthenia gravis. Dan and Lindstrom, using plasmaphoresis and immunosuppressive treatment, noted clinical improvement in idiopathic myasthenia gravis coincident with decreases in these antibody titers (10). In the majority of the previously reported cases of penicillamine-induced myasthenia syndromes, the patients ingested 1 gm of drug daily for at least 4 months before symptoms developed. Patient 1 in this report had been receiving 750 mg per day. The above association of daily dose and duration of therapy may be an artifact of methodology for the recommended dosage. Masters (4) failed to note a relationship between the dose of drug and the development of antibodies to receptor or muscle. In all cases to date, withdrawal of penicillamine was followed by recession or complete remission of the myasthenia syndrome. The need for anticholinesterase medication and the slow improvement after cessation of therapy in Patient 2 may simply have reflected prolonged treatment with penicillamine and failure to recognize the association of the myasthenia syndrome and the administration of penicillamine. Failure to recognize this syndrome may result in life threatening respiratory complications requiring a prolonged period of recovery. A myasthenia gravis syndrome may occur in patients receiving penicillamine treatment for rheumatoid arthritis. When signs of this syndrome appear, penicillamine treatment should be stopped and recovery of normal muscle function should follow. Antibodies to anti-striational and acetylcholine receptor antigens are seen in both idiopathic and penicillamine-induced myasthenia syndromes. Although penicillamine has been shown to be effective in the management of rheumatoid arthritis, its association with immunologically induced disease should temper its widespread clinical use. Penicillamine therapy also requires that the physician be familiar with these complications and be constantly alert for their appearance.
REFERENCES 1. Bucknall RC, Dixon St AJ, Glick EN, Woodland J, Zutski DW: Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. Br Med J 1:600-602, 1975 2. B’alint G, Szobar A, Temesvari P, Zahuminsky Z, Bozsoky S: Myasthenia gravis developed under D-penicillamine treatment. Scand J Rheumatol (suppl 8) Workshop 21, 1975 3. Gordon RA, Burnside JW: D-penicillamine induced myasthenia gravis in rheumatoid arthritis. Ann Intern Med 87:578, 1977 4. Czlonkowska A: Myasthenia syndrome during penicillamine administration. Br Med J 2:726-727, 1975 5. Masters CL, Dawkins RL, Zilks DJ, Simpson JA, Leedman RJ: Penicillamine associated myasthenia gravis: acetylcholine receptor and antistriational antibodies. Am J Med 63:689-694, 1977 6. Crouzet J, Camus JP, Leca AP, Guillen P, Luvre JA: Lupus induced by D-penicillamine during treatment of rheumatoid arthritis. Ann Med Interne (Paris) 125:71-79, 1974 7. Sternleib I, Bennett B, Scheinberg IH: D-penicillamine induced Goodpasture’s syndrome in Wilson’s disease. Ann Intern Med 82:673-675, 1975 8. Cucher BG, Goldman AL: Penicillamine induced polymyositis in rheumatoid arthritis. Ann Intern Med 85:6 15616, 1976 9. Schraeder PL, Peters HA, Dahl DS: Polymyositis and penicillamine. Arch Neurol 27:456457, 1972 10. Dan PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE: Plasmaphoresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 297: 11341140, 1977
WALTERR. SUNDSTROM, MD A. A. SCHUNA, RPH, MS William S. Middleton Memorial VA Hospital Madison, Wisconsin
From the William S. Middleton Memorial Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705. Supported by the Medical Research Service of the Veterans Administration. Address reprint requests to Walter R. Sundstrom, MD, William S. Middleton Memorial Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705. Submitted for publication July 20, 1978; accepted August 26, 1978.
BRIEF REPORTS
Penicillamine-induced myasthenia gravis D-penicillamine has been established as an effective agent in the management of rheumatoid arthritis. It is also used to treat patients with Wilson’s disease and cystinuria. Myasthenia gravis has been reported to occur in patients receiving penicillamine treatment for both rheumatoid arthritis (1-3) and Wilson’s disease (43). This report describes two patients who developed myasthenia gravis while receiving penicillamine for the treatment of rheumatoid arthritis. CASE REPORT Patient 1. A 60-year-old white female developed bilateral polyarthropathy involving the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrists, knees, ankles, and inetatarsophalangeal (MTP) joints. Extraarticular manifestations included fatigue, bilateral carpal tunnel syndrome, and Raynaud’s phenomenon. American Rheumatism Association functional class progressed from Class I to Class 3 between 1970 and 1976. Therapy with salicylates and nonsteroidal drugs was unsuccessful in controlling her disease. A trial of gold sodium thiomalate was complicated by oral ulcerations and generalized skin rash after a total dose of 650 mg, thus necessitating withdrawal of gold. Penicillamine (250 mg/day)’was begun in 1976 and gradually increased to 750 mg/day. Within 5 months, the functional class had improved from Class 3 to Class 1. Seven months after the initiation of therapy, unilateral ptosis, generalized muscular weakness, and masseter fatigue were noted. Within 1 month, she was unable to chew solid food and could not forcibly close her jaws after chewing for 2 to 5 minutes. Physical examination revealed ptosis of the right palpebral fissure, slight indistinct speech, and fatigue of masseter function following gum chewing. A test dose of normal saline produced no improvement. Edrophonium sulfate, 4 mg intravenously, was followed by a loss of ptosis and masseter fatigue. Electromyography was not done. Penicillamine was discontinued; anticholinesterase drugs were not administered. The symptoms of myasthenia improved over 8 weeks and have not recurred. Currently, the rheumatoid disease is managed with fenoprofen, 1800 mg/day, and prednisone, 2.5 mg/day. Patient 2. A 54-year-old male with a 30 year history of rheumatoid arthritis characterized by symmetrical polyarthropathy and joint deformity was placed on penicillamine therapy following failure with the following regimes: aspirin, nonsteroidal drugs, gold, and low dose steroids. The dose of penicillamine was gradually increased to 1.5 gm/day. This was followed by an increase in myalgias, dysgeusia, nausea, and diarrhea. Reduction of penicillamine to 750 mg was folArthritis and Rheumatism, Val. 22, No. 2 (February 1979)
lowed by cessation of these symptoms. Improvement of the rheumatoid arthritis, both subjective and objective, was noted at this time. Within 6 months (10 months following the initiation of penicillamine treatment), the patient complained of diplopia and blurred vision. Examination revealed a left third nerve paresis and bilateral ptosis, and a tensilon test confirmed the impression of myasthenia gravis. Following intravenous edrophonium, the patient’s ptosis and abnormalities of extraocular motion disappeared. Electromyography revealed a characteristic response to tetanic stimulation. Anticholinesterase medications (pyridostigmine and neostigmine) were begun, penicillamine was discontinued, and the myasthenia improved. During the subsequent clinical course, myasthenia crisis was precipitated by a flu syndrome and the patient required assisted ventilation and hospitalization. Penicillamine was resumed when the underlying arthropathy worsened 2 months later. The drug was discontinued permanently following the first published report of penicillamine associated with the myasthenia syndrome. There was a gradual improvement manifested by clearing of ptosis, third nerve paresis, difficulty in swallowing, and weakness of the neck extensors. The patient has been off penicillamine for 26 months and continues on 540 mg of pyridostigmine and 60 mg of neostigmine daily.
DISCUSSION The occurrence of myasthenia gravis in association with rheumatoid arthritis appears to be rare, although it is difficult to document. Our experience reveals only one case of idiopathic myasthenia gravis in 400 cases of rheumatoid arthritis (0.25%). Others have demonstrated an increase in the frequency of rheumatoid arthritis in myasthenia gravis (1). However, it is felt that this is related to the “two disease fallacy” concept, i.e., patients with two diseases are more likely to be admitted to a hospital, to attract attention, and to be mentioned in the literature. The infrequency of rheumatoid arthritis associated with myasthenia suggests that it occurs by chance and not as an associated immunologic phenomenon. The recent observation that reversible myasthenia gravis apparently occurs more frequently in rheumatoid arthritis patients receiving penicillamine suggests that penicillamine is a causal factor. The relationship of clinical syndromes indistinguishable from systemic lupus erythematosus (6), Goodpasture’s syndrome (7), and polymyositis (8,9) in patients receiving penicillamine further implicates the ability of penicillamine to induce or unmask abnormalities of immune function. Recently, Masters (4) studied 56 patients receiving penicillamine for rheumatoid arthritis. None of the patients had overt myasthenia gravis. Two complained
198
of fatigue and had evidence on electromyography of defective neuromuscular function. Anti-striational antibodies were found in the sera of 11 patients, one of whom had a significantly elevated anti-skeletal muscle antibody and a slight increase in acetylcholine receptor antibody. In addition, Masters studied the sera of 5 patients who developed clinical myasthenia gravis while undergoing penicillamine treatment for rheumatoid arthritis. Anti-acetylcholine receptor antibodies were present in 4 of these 5 patients (5). These antibodies are implicated as a pathogenic factor in myasthenia gravis. Dan and Lindstrom, using plasmaphoresis and immunosuppressive treatment, noted clinical improvement in idiopathic myasthenia gravis coincident with decreases in these antibody titers (10). In the majority of the previously reported cases of penicillamine-induced myasthenia syndromes, the patients ingested 1 gm of drug daily for at least 4 months before symptoms developed. Patient 1 in this report had been receiving 750 mg per day. The above association of daily dose and duration of therapy may be an artifact of methodology for the recommended dosage. Masters (4) failed to note a relationship between the dose of drug and the development of antibodies to receptor or muscle. In all cases to date, withdrawal of penicillamine was followed by recession or complete remission of the myasthenia syndrome. The need for anticholinesterase medication and the slow improvement after cessation of therapy in Patient 2 may simply have reflected prolonged treatment with penicillamine and failure to recognize the association of the myasthenia syndrome and the administration of penicillamine. Failure to recognize this syndrome may result in life threatening respiratory complications requiring a prolonged period of recovery. A myasthenia gravis syndrome may occur in patients receiving penicillamine treatment for rheumatoid arthritis. When signs of this syndrome appear, penicillamine treatment should be stopped and recovery of normal muscle function should follow. Antibodies to anti-striational and acetylcholine receptor antigens are seen in both idiopathic and penicillamine-induced myasthenia syndromes. Although penicillamine has been shown to be effective in the management of rheumatoid arthritis, its association with immunologically induced disease should temper its widespread clinical use. Penicillamine therapy also requires that the physician be familiar with these complications and be constantly alert for their appearance.
REFERENCES 1. Bucknall RC, Dixon St AJ, Glick EN, Woodland J, Zutski DW: Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. Br Med J 1:600-602, 1975 2. B’alint G, Szobar A, Temesvari P, Zahuminsky Z, Bozsoky S: Myasthenia gravis developed under D-penicillamine treatment. Scand J Rheumatol (suppl 8) Workshop 21, 1975 3. Gordon RA, Burnside JW: D-penicillamine induced myasthenia gravis in rheumatoid arthritis. Ann Intern Med 87:578, 1977 4. Czlonkowska A: Myasthenia syndrome during penicillamine administration. Br Med J 2:726-727, 1975 5. Masters CL, Dawkins RL, Zilks DJ, Simpson JA, Leedman RJ: Penicillamine associated myasthenia gravis: acetylcholine receptor and antistriational antibodies. Am J Med 63:689-694, 1977 6. Crouzet J, Camus JP, Leca AP, Guillen P, Luvre JA: Lupus induced by D-penicillamine during treatment of rheumatoid arthritis. Ann Med Interne (Paris) 125:71-79, 1974 7. Sternleib I, Bennett B, Scheinberg IH: D-penicillamine induced Goodpasture’s syndrome in Wilson’s disease. Ann Intern Med 82:673-675, 1975 8. Cucher BG, Goldman AL: Penicillamine induced polymyositis in rheumatoid arthritis. Ann Intern Med 85:6 15616, 1976 9. Schraeder PL, Peters HA, Dahl DS: Polymyositis and penicillamine. Arch Neurol 27:456457, 1972 10. Dan PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE: Plasmaphoresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 297: 11341140, 1977
WALTERR. SUNDSTROM, MD A. A. SCHUNA, RPH, MS William S. Middleton Memorial VA Hospital Madison, Wisconsin
From the William S. Middleton Memorial Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705. Supported by the Medical Research Service of the Veterans Administration. Address reprint requests to Walter R. Sundstrom, MD, William S. Middleton Memorial Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705. Submitted for publication July 20, 1978; accepted August 26, 1978.
