3. 4.
5.
6.
in relation to typhoid fever. Surg Gynecol Obstet 23: 119, 1916 GIACCAI L, IDuss H: Osteomyelitis due to s.dmonella infection. J Pediatr 41: 73, 1952 PORAT 5, BREZIS M, KOPOLOVIC J: Salmonella-typhi osteomyelitis long after a fracture - case report. J Bone Joint Surg [Am] 59: 687, 1977 DAVIDSON PT, HOROWITZ I: Skeletal tuberculosis. A review with patient presentations and discussion. Am J Med 48: 77, 1970 HuNT DD: Problems in diagnosing osteoarticular tuberculosis. JAMA 190: 95, 1964
7. WALLACE R, COHEN AS: Tuberculous arthritis. A report on two cases with review of biopsy and synovial fluid findings. Am .1 Med 61: 277, 1976 8. BERNEY 5, GOLDSTEIN M, BIsHKo F:
Clinical and diagnostic features of tuberculous arthritis. Am J Med 53: 36, 1972 9. HonosoN AR, SMITH TK: Tuberculosis of the wrist. Clin C'rthop 83: 73, 1972 10. BoswoRm
DM,
DELLA PIETRA A,
FARRELL RE: Classic - streptomycin in tuberculous bone and joint lesions with mixed infection and sinuses. Clin Orthop 116: 2, 1976
11. GIRDLESTONE GR:
Tuberculosis of
Bone and Joint, 3rd ed, SOMERVILLE
EW, WILKINSON MC (eds), Oxford U Pr, New York, 1965, p 41 12. DAVID JR, BLACK RL: Salmonella arthritis. Medicine (Baltimore) 3: 385, 1960 13. WALDVOGEL FA, MEDOFF G, SWARTZ
MN: Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects (third of three parts). N Engl J Med 282: 316, 1970 14. KAUFMANN E: Pathology for Students and Practitioners, vol 2, REIMANN SP (trans), Blakiston, New York, 1929, p 1096
Cholestasis associated with D*penicillamine therapy for rheumatoid arthritis B. DANIEL MCLEOD,* MD; T. DOUGLAS KINSELLA,t MD, FRCP[C]
The use of D-penicillamine in the treatment of rheumatoid arthritis has led to the recognition of a variety of adverse effects, such as proteinuna, nephrotic syndrome, thrombocytopenia, skin rashes, dysgeusia, gynecomastia and several autoimmune disorders, including a systemiclupus-erythematosus-like syndrome, polymyositis and myasthenia gravis.1 Recently a fatal case of cholestatic jaundice secondary to D-penicillamine therapy for rheumatoid arthritis was reported.1 We have encountered a patient who recovered from this complication when D-penicillamine therapy was withdrawn; her case is described below. Case report A 41-year-old woman was admitted to our rheumatic disease unit From the University of Calgary rheumatic disease unit, Calgaty General Hospital *Resident in rheumatology; fellow of the Canadian Arthritis Society tProfessor of medicine and director, University of Calgary rheumatic disease unit; associate of the Canadian Arthritis Society Reprint requests to: Dr. B. Daniel McLeod, Rheumatic disease unit, Calgary General Hospital, 841 Centre Ave. NE, Calgary, Alta. T2E OA1
because of jaundice. Prior to her initial evaluation at the unit's clinic 3 weeks earlier, prednisone, 10 mg/d, and indomethacin, 50 mg three times a day, had been prescribed for rheumatoid arthritis that had begun 20 years previously. She had been taking an average of four 325-mg tablets of acetaminophen per day for pain for many years. Therapy with D-penicillamine, 250 mg/d, had been instituted after the initial evaluation. Two weeks after the initiation of D-penicillamine therapy a pruritic, erythematous, maculopapular rash appeared and she experienced acute epigastric pain associated with nausea and vomiting. The drug was then discontinued, and the rash and abdominal pain resolved. However, she continued to have pruritus and became jaundiced approximately 3 weeks after the initiation of D-penicillamine therapy. She had not noted any change in colour of the urine or stool. In the past she had received two courses of chrysotherapy, without adverse or beneficial effects. She had also undergone tendon repair of the left thumb, partial gastrectomy because of a pefforated peptic ulcer and total hip replacement. She was noted to have advanced
deformities of rheumatoid arthritis, with ulnar deviation and boutonniere deformities of the hands, a flexion contracture of the right knee and flexion deformities of the toes. Active synovitis was present in her elbows, wrists, metacarpophalangeal joints and knees. Jaundice was clinically apparent, and numerous excoriations of the skin were noted. No other clinical abnormalities were noted. On the day of admission the hemoglobin value was 10.7 g/dl, the platelet count 714 x 10./l, the leukocyte count 7.2 x 10./l (with 80% polymorphonuclear cells, 14% lymphocytes, 4% monocytes, 1% eosinophils and 1% band forms) and the erythrocyte sedimentation rate 55 mm/h (Westergren). The following serum values were noted: alkaline phosphatase 1132 lU/I (normal 85 to 210 IU/l), glutamic oxaloacetic transaminase (SGOT) 117 IU/l (normal 0 to 25 lU/l), lactate dehydrogenase 109 lU/l (normal 0 to 74 IU/l), total biirubin 56 p.mol/l (3.3 mg/dl) and direct-reacting bilirubin 41 .mol/l (2.4 mg/dl) (normal less than 17 .mol/l [1 mg/dl]). The prothrombin time was 9.5 seconds (control time 10.9 seconds) and the partial thromboplastin time 25 seconds (con-
CMA JOURNAL/APRIL 21, 1979/VOL. 120 965
trol time 32.5 seconds). A test for been described in some patients.3'4 hepatitis B surface antigen gave nega- In view of these considerations, and tive results. Immediately before the because of the drug's toxicity and initiation of D-penicillamine therapy the uncertainty regarding the optithe alkaline phosphatase, SGOT, lac- mum dose, it has been recommended tate dehydrogenase and bilirubin only for patients who have not benefited from conventional therapy.4 values had been normal. Our patient's typical cholestatic After the patient was admitted to the unit an intravenous cholecysto- jaundice was probably drug-induced gram showed no extrahepatic biiary since the intravenous cholecystogram obstruction and a normal gallbladder. was normal. It was considered most A liver biopsy done a week after likely that D-penicillamine was the admission gave evidence of chole- causative agent, although some of the stasis without significant abnormal- other medications she was receiving ities of the parenchyma or cellular are known to cause hepatic toxic infiltration of the parenchyma or bile effects. Corticosteroids may be associated ducts. The jaundice cleared while the pa- with fatty infiltration of the liver.5 tient was in hospital, and when she However, liver biopsy in our patient was discharged, 9 days after admis- did not show fatty infiltration and, sion, the following serum values were to our knowledge, corticosteroids recorded: alkaline phosphatase 1899 have not been implicated as a cause IU/l, SGOT 86 lU/l and bilirubin of drug-induced cholestasis. Hepatic necrosis is a well known 27 p.mol/l (1.6 mg/dl). The medications she was to take were predni- complication of acetaminophen oversone, 10 mg and 7.5 mg on alternate dose,6 and, rarely, hepatic damage days, and acetaminophen, 325 mg as has been reported from long-term administration of the drug in therapeuneeded for pain. Two weeks after the patient's dis- tic doses.7 However, in the latter situcharge the serum bilirubin value was ation hepatocellular damage rather normal, but the alkaline phosphatase than cholestasis has been noted. and SGOT values were still elevated, Furthermore, since our patient was at 657 and 341 lU/l respectively. able to resume taking acetaminophen A further 11 weeks later the alkaline without recurrence of cholestasis it phosphatase and SGOT values had is improbable that this agent was implicated in her acute illness. returned to normal. Indomethacin has also been rarely associated with hepatic damage. Discussion Acute yellow atrophy occurred in In the treatment of rheumatoid ar- one child with juvenile chronic arththritis D-penicillamine is becoming ritis,8 and cholestasis developed in accepted as an effective agent.1 How- another person treated with both inever, its use is associated with signi- domethacin and D-penicillamine, ficant toxic effects, including aplastic which suggests that the combination anemia, thrombocytopenia, leuko- of these medications may be hepapenia, proteinuria that may be great totoxic.9 If it does occur, additive enough to produce the nephrotic syn- hepatotoxicity of these two drugs drome, gastrointestinal disturbances might account for the occurrence of and rashes.3 These adverse reactions cholestasis in our patient. However, may be reversed by the cessation of at least two cases have been reported therapy and may be anticipated by of cholestasis in patients treated with careful clinical and laboratory mon- D-penic.lllamine without the concuritoring.1'4 However, the fact that long- rent use of indomethacin; one was a term therapy with D-penicillamine patient wth scleroderma1 and the has not provoked such reactions does other a patient with rheumatoid arthnot ensure its safety since a variety ritis.2 Finally, Walshe" has briefly of drug-induced autoimmune dis- described a patient in whom choleorders such as myasthenia gravis and stasis developed during D-penicillasystemic lupus erythematosus have mine therapy for Wilson's disease. 966 CMA JOURNAL/APRIL 21, 1979/VOL. 120
The frequency of cholestasis in patients treated with D-penicillamine is not known, but in several large series this complication has not been re.. ported.3'4'11 However, in a recent study of D-penicillamine therapy for rheumatoid arthritis, two patients receiving the drug in a low dose (less than 45 mg/d) were noted to have elevations of SGOT and serum glutamic pyruvic transaminase values, but apparently no frank evidence of hepatotoxic effects was looked for or found.1' Thus, physicians prescribing D-penicillamine therapy should be alert to its potential hepatotoxicity, and speculation about the prevalence of this complication should be reserved. References 1. JAFFE IA: D-penicillamine. Bull Rheum Dis 28: 948, 1978 2. BARZILAI D, DICKSTEIN G, ENAT R, Ct al: Cholestatic jaundice caused by D-penicilamine. Ann Rheum Dis 37: 98, 1978 3. WEiss AS, MARKENSON JA, WEISs MS, et al: Toxicity of n-penicillamine in rheumatoid arthritis. A report of 63 patients including two with aplastic anemia and one with the nephrotic syndrome. An? J Med 64: 114, 1978 4. HILL HFN: Treatment of rheumatoid arthritis with penicillamine. Semin Arthritis Rheum 6: 361, 1977 5. ALPERS DH, ISSELBACHER KJ: Fatty liver: biochemical and clinical aspects, in Diseases of the Liver, 4th ed, SCHIFF L (ed), Lippincott, Philadelphia, 1975, pp 815-29 6. AMEER B, GREENBLATr DJ: Acetaminophen. Ann intern Med 87: 202, 1977 7. BONKOWSKY HL, MUDGE GH, McMURTRY RI: Chronic hepatic inflammation and fibrosis due to low doses of paracetamol. Lancet 1: 1016, 1978 8. KELSEY WM, SCHARYJ M: Fatal hepatiti. probably due to indomethacin. JAMA 199: 586, 1967 9. SIEGMUND H: Intrahepatische Cholestase nach einer Behandlung mit Dpenicillamin und Indomethacin. Med Welt 27: 172, 1976 10. RAUS R, WEBER 5, BONI A: Allergisch-toxische Leberschadigung durch D-penicillamin. Schweiz Med Wochenschr 102: 1226, 1972 11. WALSHE JM: Toxic reactions to penicillamine in patients with Wilson's disease. Postgrad Med I (suppl): 6, 1968 12. SHIOKAWA Y, HoRIucHI Y, HONMX M, et al: Clinical evaluation of Dpenicillamine by multicentric doubleblind comparative study in chronic rheumatoid arthritis. Arthritis Rheum 20: 1464, 1977
5.
6.
in relation to typhoid fever. Surg Gynecol Obstet 23: 119, 1916 GIACCAI L, IDuss H: Osteomyelitis due to s.dmonella infection. J Pediatr 41: 73, 1952 PORAT 5, BREZIS M, KOPOLOVIC J: Salmonella-typhi osteomyelitis long after a fracture - case report. J Bone Joint Surg [Am] 59: 687, 1977 DAVIDSON PT, HOROWITZ I: Skeletal tuberculosis. A review with patient presentations and discussion. Am J Med 48: 77, 1970 HuNT DD: Problems in diagnosing osteoarticular tuberculosis. JAMA 190: 95, 1964
7. WALLACE R, COHEN AS: Tuberculous arthritis. A report on two cases with review of biopsy and synovial fluid findings. Am .1 Med 61: 277, 1976 8. BERNEY 5, GOLDSTEIN M, BIsHKo F:
Clinical and diagnostic features of tuberculous arthritis. Am J Med 53: 36, 1972 9. HonosoN AR, SMITH TK: Tuberculosis of the wrist. Clin C'rthop 83: 73, 1972 10. BoswoRm
DM,
DELLA PIETRA A,
FARRELL RE: Classic - streptomycin in tuberculous bone and joint lesions with mixed infection and sinuses. Clin Orthop 116: 2, 1976
11. GIRDLESTONE GR:
Tuberculosis of
Bone and Joint, 3rd ed, SOMERVILLE
EW, WILKINSON MC (eds), Oxford U Pr, New York, 1965, p 41 12. DAVID JR, BLACK RL: Salmonella arthritis. Medicine (Baltimore) 3: 385, 1960 13. WALDVOGEL FA, MEDOFF G, SWARTZ
MN: Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects (third of three parts). N Engl J Med 282: 316, 1970 14. KAUFMANN E: Pathology for Students and Practitioners, vol 2, REIMANN SP (trans), Blakiston, New York, 1929, p 1096
Cholestasis associated with D*penicillamine therapy for rheumatoid arthritis B. DANIEL MCLEOD,* MD; T. DOUGLAS KINSELLA,t MD, FRCP[C]
The use of D-penicillamine in the treatment of rheumatoid arthritis has led to the recognition of a variety of adverse effects, such as proteinuna, nephrotic syndrome, thrombocytopenia, skin rashes, dysgeusia, gynecomastia and several autoimmune disorders, including a systemiclupus-erythematosus-like syndrome, polymyositis and myasthenia gravis.1 Recently a fatal case of cholestatic jaundice secondary to D-penicillamine therapy for rheumatoid arthritis was reported.1 We have encountered a patient who recovered from this complication when D-penicillamine therapy was withdrawn; her case is described below. Case report A 41-year-old woman was admitted to our rheumatic disease unit From the University of Calgary rheumatic disease unit, Calgaty General Hospital *Resident in rheumatology; fellow of the Canadian Arthritis Society tProfessor of medicine and director, University of Calgary rheumatic disease unit; associate of the Canadian Arthritis Society Reprint requests to: Dr. B. Daniel McLeod, Rheumatic disease unit, Calgary General Hospital, 841 Centre Ave. NE, Calgary, Alta. T2E OA1
because of jaundice. Prior to her initial evaluation at the unit's clinic 3 weeks earlier, prednisone, 10 mg/d, and indomethacin, 50 mg three times a day, had been prescribed for rheumatoid arthritis that had begun 20 years previously. She had been taking an average of four 325-mg tablets of acetaminophen per day for pain for many years. Therapy with D-penicillamine, 250 mg/d, had been instituted after the initial evaluation. Two weeks after the initiation of D-penicillamine therapy a pruritic, erythematous, maculopapular rash appeared and she experienced acute epigastric pain associated with nausea and vomiting. The drug was then discontinued, and the rash and abdominal pain resolved. However, she continued to have pruritus and became jaundiced approximately 3 weeks after the initiation of D-penicillamine therapy. She had not noted any change in colour of the urine or stool. In the past she had received two courses of chrysotherapy, without adverse or beneficial effects. She had also undergone tendon repair of the left thumb, partial gastrectomy because of a pefforated peptic ulcer and total hip replacement. She was noted to have advanced
deformities of rheumatoid arthritis, with ulnar deviation and boutonniere deformities of the hands, a flexion contracture of the right knee and flexion deformities of the toes. Active synovitis was present in her elbows, wrists, metacarpophalangeal joints and knees. Jaundice was clinically apparent, and numerous excoriations of the skin were noted. No other clinical abnormalities were noted. On the day of admission the hemoglobin value was 10.7 g/dl, the platelet count 714 x 10./l, the leukocyte count 7.2 x 10./l (with 80% polymorphonuclear cells, 14% lymphocytes, 4% monocytes, 1% eosinophils and 1% band forms) and the erythrocyte sedimentation rate 55 mm/h (Westergren). The following serum values were noted: alkaline phosphatase 1132 lU/I (normal 85 to 210 IU/l), glutamic oxaloacetic transaminase (SGOT) 117 IU/l (normal 0 to 25 lU/l), lactate dehydrogenase 109 lU/l (normal 0 to 74 IU/l), total biirubin 56 p.mol/l (3.3 mg/dl) and direct-reacting bilirubin 41 .mol/l (2.4 mg/dl) (normal less than 17 .mol/l [1 mg/dl]). The prothrombin time was 9.5 seconds (control time 10.9 seconds) and the partial thromboplastin time 25 seconds (con-
CMA JOURNAL/APRIL 21, 1979/VOL. 120 965
trol time 32.5 seconds). A test for been described in some patients.3'4 hepatitis B surface antigen gave nega- In view of these considerations, and tive results. Immediately before the because of the drug's toxicity and initiation of D-penicillamine therapy the uncertainty regarding the optithe alkaline phosphatase, SGOT, lac- mum dose, it has been recommended tate dehydrogenase and bilirubin only for patients who have not benefited from conventional therapy.4 values had been normal. Our patient's typical cholestatic After the patient was admitted to the unit an intravenous cholecysto- jaundice was probably drug-induced gram showed no extrahepatic biiary since the intravenous cholecystogram obstruction and a normal gallbladder. was normal. It was considered most A liver biopsy done a week after likely that D-penicillamine was the admission gave evidence of chole- causative agent, although some of the stasis without significant abnormal- other medications she was receiving ities of the parenchyma or cellular are known to cause hepatic toxic infiltration of the parenchyma or bile effects. Corticosteroids may be associated ducts. The jaundice cleared while the pa- with fatty infiltration of the liver.5 tient was in hospital, and when she However, liver biopsy in our patient was discharged, 9 days after admis- did not show fatty infiltration and, sion, the following serum values were to our knowledge, corticosteroids recorded: alkaline phosphatase 1899 have not been implicated as a cause IU/l, SGOT 86 lU/l and bilirubin of drug-induced cholestasis. Hepatic necrosis is a well known 27 p.mol/l (1.6 mg/dl). The medications she was to take were predni- complication of acetaminophen oversone, 10 mg and 7.5 mg on alternate dose,6 and, rarely, hepatic damage days, and acetaminophen, 325 mg as has been reported from long-term administration of the drug in therapeuneeded for pain. Two weeks after the patient's dis- tic doses.7 However, in the latter situcharge the serum bilirubin value was ation hepatocellular damage rather normal, but the alkaline phosphatase than cholestasis has been noted. and SGOT values were still elevated, Furthermore, since our patient was at 657 and 341 lU/l respectively. able to resume taking acetaminophen A further 11 weeks later the alkaline without recurrence of cholestasis it phosphatase and SGOT values had is improbable that this agent was implicated in her acute illness. returned to normal. Indomethacin has also been rarely associated with hepatic damage. Discussion Acute yellow atrophy occurred in In the treatment of rheumatoid ar- one child with juvenile chronic arththritis D-penicillamine is becoming ritis,8 and cholestasis developed in accepted as an effective agent.1 How- another person treated with both inever, its use is associated with signi- domethacin and D-penicillamine, ficant toxic effects, including aplastic which suggests that the combination anemia, thrombocytopenia, leuko- of these medications may be hepapenia, proteinuria that may be great totoxic.9 If it does occur, additive enough to produce the nephrotic syn- hepatotoxicity of these two drugs drome, gastrointestinal disturbances might account for the occurrence of and rashes.3 These adverse reactions cholestasis in our patient. However, may be reversed by the cessation of at least two cases have been reported therapy and may be anticipated by of cholestasis in patients treated with careful clinical and laboratory mon- D-penic.lllamine without the concuritoring.1'4 However, the fact that long- rent use of indomethacin; one was a term therapy with D-penicillamine patient wth scleroderma1 and the has not provoked such reactions does other a patient with rheumatoid arthnot ensure its safety since a variety ritis.2 Finally, Walshe" has briefly of drug-induced autoimmune dis- described a patient in whom choleorders such as myasthenia gravis and stasis developed during D-penicillasystemic lupus erythematosus have mine therapy for Wilson's disease. 966 CMA JOURNAL/APRIL 21, 1979/VOL. 120
The frequency of cholestasis in patients treated with D-penicillamine is not known, but in several large series this complication has not been re.. ported.3'4'11 However, in a recent study of D-penicillamine therapy for rheumatoid arthritis, two patients receiving the drug in a low dose (less than 45 mg/d) were noted to have elevations of SGOT and serum glutamic pyruvic transaminase values, but apparently no frank evidence of hepatotoxic effects was looked for or found.1' Thus, physicians prescribing D-penicillamine therapy should be alert to its potential hepatotoxicity, and speculation about the prevalence of this complication should be reserved. References 1. JAFFE IA: D-penicillamine. Bull Rheum Dis 28: 948, 1978 2. BARZILAI D, DICKSTEIN G, ENAT R, Ct al: Cholestatic jaundice caused by D-penicilamine. Ann Rheum Dis 37: 98, 1978 3. WEiss AS, MARKENSON JA, WEISs MS, et al: Toxicity of n-penicillamine in rheumatoid arthritis. A report of 63 patients including two with aplastic anemia and one with the nephrotic syndrome. An? J Med 64: 114, 1978 4. HILL HFN: Treatment of rheumatoid arthritis with penicillamine. Semin Arthritis Rheum 6: 361, 1977 5. ALPERS DH, ISSELBACHER KJ: Fatty liver: biochemical and clinical aspects, in Diseases of the Liver, 4th ed, SCHIFF L (ed), Lippincott, Philadelphia, 1975, pp 815-29 6. AMEER B, GREENBLATr DJ: Acetaminophen. Ann intern Med 87: 202, 1977 7. BONKOWSKY HL, MUDGE GH, McMURTRY RI: Chronic hepatic inflammation and fibrosis due to low doses of paracetamol. Lancet 1: 1016, 1978 8. KELSEY WM, SCHARYJ M: Fatal hepatiti. probably due to indomethacin. JAMA 199: 586, 1967 9. SIEGMUND H: Intrahepatische Cholestase nach einer Behandlung mit Dpenicillamin und Indomethacin. Med Welt 27: 172, 1976 10. RAUS R, WEBER 5, BONI A: Allergisch-toxische Leberschadigung durch D-penicillamin. Schweiz Med Wochenschr 102: 1226, 1972 11. WALSHE JM: Toxic reactions to penicillamine in patients with Wilson's disease. Postgrad Med I (suppl): 6, 1968 12. SHIOKAWA Y, HoRIucHI Y, HONMX M, et al: Clinical evaluation of Dpenicillamine by multicentric doubleblind comparative study in chronic rheumatoid arthritis. Arthritis Rheum 20: 1464, 1977
