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Metal antagonists
R.H.B. Meyboom and I.A. Jaffe
24 PeniciUamine (SED-IO,409; SEDA-8, 235; SEDA-9, 223; SEDA-IO, 217) General Under the title Pbnicillamine, bilan d'une expbrience, the second part of the VIII French Conference of Rheumatology (Paris, 19-20 March, 1985) was devoted to peniciUamine (lCX). Camus et al on that occasion reviewed the history and the use of penicillamine in human disease (2R). Valat et al presented the results of a 5-year follow-up study on 104 patients receiving penicillamine for rheumatoid arthritis. Their findings confirm those of earlier studies, that penicillamine is effective in rheumatoid arthritis but that its use is limited by frequent side effects and relapses of the disease (3CR). After 5 years, only 26% of the patients were still taking penicillamine with satisfactory results, 45% had stopped the drug because of side effects and 14.5% did so because of insufficient effect (the remaining 14.5% withdrew from follow-up). Withdr~awal due to side effects largely occurred during the first 2 years of the treatment and rarely thereafter. Predominant side effects were, in decreasing frequency, proteinuria, skin reactions, and blood dyscrasias. A welcome up-to-date overview of the chemistry, kinetics and the complex pharmacology of penicillamine has been provided by Howard-Lock et al (4~). Penicillamine has 3 major biochemical effects: (a) The formation of disulfide links with other sulfhydryl compounds, as the result of either an oxidation or an exchange reaction. This effect is successfully applied in the treatment of cystinuria. (b) Condensation with carbonyl compounds (aldehydes and ketones) to give substituted thiazolidine carboxylic acids, causing inhibition of collagen cross-linking. This property is responsible for the 'lathyrogenic' effect on the skin of high doses of penicillamine, and is experimentally used in the treatment of scleroderma and fibrotic disorders and for acetaldehyde detoxification. (c) Formation of complexes or chelates with metals. Firstly, this effect is used in the treatment of metal Side Effects of Drugs Annual 11 M.N.G. Dukes,editor 9 ElsevierSciencePublishersB.V., 1987
Metal antagonists poisoning and of Wilson's diseasr Secondly, complexes with trace metals (copper) may interfere with enzymatic processes (e.g. with superoxide dismutase) and may influence the production and scavenging of oxygen-derived free radicals and the process of inflammation. Recent work has provided further data on the effect of penicillamine, be it direct or indirect, on the production of superoxides (5cx, 6cR) and seems promising with regard to the unraveling of the influence o f this drug on rheumatoid arthritis and on immune processes. Jaffe has discussed the apparent similarity of the patterns of side effects of various sulfhydryl compounds (7R). In this light it is interesting that, in accordance with previous reports (SEDA-8, 236; SEDA-9, 223), it was found in a study of 10 years duration that the responses to a sulflaydryl drug (penicillamine, sodium aurothiomalate and aurothioglucose or pyritinol), either therapeutic or adverse, are - with the exception of proteinuria - largely independent of earlier experiences with one of the other drugs in this group (8cx). An interesting new approach to the study of the side effects of penicillamine is the collaborative study by regional 'pharmacovigilance' centers in France (9cR). Over a 4-year period, 78 reports were collected on suspected adverse reactions to penicillamine. There was a predominance of blood dyscrasias (23 cases), pemphigus-like eruptions (9 cases), nephrotic syndrome (5) and myasthenia (5 cases). Noteworthy too, are 2 cases of myositis and 1 of Goodpasture's syndrome. The 5 cases of 'pulmonary fibrosis', however, need further clarification. The emerging pattern of reactions is influenced by the fact that more severe reactions are more prone to be reported than are mild effects. The French study shows that certain complications of penicillamine ,which have only occasionally been described in the literature are in fact encountered in medical practice. Also interesting was the comparison in the French study with 23 case-reports on pyritinol (see below). A large trial with 259 patients has yielded a similar pattern of adverse reactions to penicillamine in patients with systemic sclerosis as
212 compared with rheumatoid arthritis (10cR). 47% of the patients had side effects and 29% of the patients had to stop the drug for this reason. Skin reactions, proteinuria, and thrombo- and leukopenia predominated. There were 4 patients with pemphigus and also 4 with myasthenia gravis, attributed to the use of penicillamine. Penicillamine has not been found effective in biliary cirrhosis (11 cR, 12eR) or ankylosing spondylitis (13oR). HLA antigens (SEDA-8, 235; SEDA-IO, 217) The association between HLA antigens and the occurrence of adverse reactions to penicillamine has been reviewed by Bardin et al (14R). The most important finding in this respect is that the antigens B8 and DR3 are associated with nephropathy. In another series of 141 patients receiving either gold or penicillamine, the relative risks of DR3-positive patients developing skin reactions or proteinuria were calculated to be 10.5 and 7 respectively as compared with DR3 negatives (15CR). The frequency of DR7 antigen in patients with side effects, on the other hand, was significantly decreased, suggesting a protective role for this antigen. Speerstra et al have found a strong association between antigens B8 and DR3 and the development of hematological reactions to aurothioglucose, but in the penicillamine group this association did not reach significance (16cR). By contrast, in the group of patients with hematological reactions to penicillamine there was an increased incidence of antigen DR4 (all patients with thrombocytopenia were DR4positive), and the authors concluded that the HLA phenotype contributing to an increased risk may be different for these 2 antirheumatic drugs (16cR). In summary, the study of HLA phentoypes in patients experiencing side effects with penicillamine is a very interesting scientific issue, but has little value for the monitoring of individual patients treated with this drug. The reader may like to compare this conclusion with that presented by Riel in Chapter 23 of this volume.
Respiratory tract Three further patients have been reported with severe and irreversible
bronchiolitis obliterans, developed within 4-8 months of treatment with penicillamine (in doses not exceeding 600mg daily) (17cR). As has been pointed out in SEDA-8 (p. 236), however, it is doubtful whether this association is causal. Another article (18) refers to the same patients.
Chapter 24 R.H.B. Meyboom and LA. Jaffe From Japan came a report on a patient with probably penicillamine-induced eosinophilic pneumonitis (19ca). Another case-report describes the simultaneous development of pneumonitis, hepatitis, rash, and fever after 10 days use of penicillamine (250 mg daily) (see 'Liver') (20cR). The causal relationship was established by a relapse on inadvertent re-exposure to penicillamine 5 months later.
Hematological
In a collaborative study of regional drug monitoring centers in France, hematological reactions (thrombocytopenia, granulocytopenia, and pancytopenia) predominated with altogether 22 cases in a total of 78 case-reports (9c). In another French series 9 of 104 patients experienced hematological reactions, including 2 patients with aplastic anemia, which ran a fatal course in 1 (3c). In a series of 259 patients with systemic sclerosis, the use of penicillamine was associated with thrombocytopenia in 10 and with leukopenia in 6 subjects (10r Henzgen and Hein had 2 patients with blood dyscrasias in their series of 34 patients (21"). One patient had agranulocytosis developing within 4 weeks' use of peniciiiamine 300 mg; the other patient had transient pancytopenia. Hematological side effects can appear quite rapidly. Umeki et al described the development of profound granulocytopenia with rash and fever in a 12-year-old girl, after only 7 days of treatment with penicillamine (800mg) for Wilson's disease (22CR). The role of penicillamine was demonstrated by the rapid recovery on withdrawal of penicillamine and a subsequent relapse of granulocytopenia after re-exposure to the drug."The lymphocyte transformation rate of lymphocyte cultures in the presence of penicillamine was 3 times higher than in lymphocytes that had not been exposed to penicillamine. This observation suggests that penicillamine-induced granulocytopenia is a delayed type hypersensitivity reaction. In conclusion, blood dyscrasias are relatively frequent complications to penicillamine, may develop suddenly, and are potentially lifethreatening. The development was described of a nonHodgkin's lymphoma in a patient with rheumatoid arthritis undergoing treatment with penicillamine, but no relationship was suspected (23c~). Interestingly, there was a remission of arthritis after chemotherapy for the lymphoma. Liver An excellent case-report illustrates the fact that cholestatic hepatitis, however rare, can
Metal antagonists Chapter24 occur as a complication to peniciUamine (24cR). The patient simultaneously had fever and a rash. The comprehensive case-report by Kumar et al is in several respects of interest (20ca). This patient, a 45-year-old woman, was admitted with fever, rash and severe dyspnea, developing 10 days after starting treatment with penicillamine and naproxen (250 and 1000mg daily, respectively) for rheumatoid arthritis. The chest X-ray showed bilateral fluffy shadows, and a diagnosis of acute hypersensitivity pneumonitis was made. Both drugs were discontinued and a short course of prednisone given. The respiratory symptoms rapidly disappeared, but fever and rash persisted for a few days and in addition cholestatic jaundice developed. No extrahepatic cause for the cholestasis was found. The patient recovered fully over a period of 4 weeks and was subsequently treated with naproxen alone without problems. An inadvertent re-exposure to penicillamine, however, was followed by a second attack of dyspnea and jaundice, providing the proof that penicillamine was the factor responsible. Urinary system Stein et al have now presented details of 26 patients with penicillamineassociatedproteinuria, i.e. 9% out of a series of 300 patients (25cR). In 10 patients proteinuria exceeded 3.5 g/24h. A nephrotic syndrome developed in 3 patients and hypertension in 1. Although 4 patients had a transient increase in serum creatinine, no renal in~atticiency occurred. Eight of the patients concomitantly had a skin rash. Proteinuria lasted for an average of 5.5 months but was reversible in all patients, despite continuation of penicillamine in 4 subjects. In 1 patient a renal biopsy was taken, revealing membranous glomerulonephritis with dense intramembranous deposits on electron microscopy, identified as IgG and C3 on immunofluorescent staining. This is the usual picture in such patients. Predisposing factors were previous gold nephropathy and the presence of HLA antigens DR3 and B8. An excellent case-report by Rehan and Johnson is unusual in that the predominant finding was deposition of IgM (instead of IgG) in the mesangial regions, i.e. the picture of the so-called IgM nephropathy or mesangial proliferative glomerulonephritis (26c~). In this patient, who had been taking only 250 mg penicillamine for 8 months, the rapid disappearance of proteinuria after stopping penicillamine was strongly suggestive of a causal involvement of the drug. In 2 recent reports, proliferative glomerulonephritis, presumably penicillamine-induced, had a fatal outcome (27cR, 28cR). In 1 case (27) a concomitant hemorrhagic pneumonitis was
213 suggestive of the presence of Goodpasture's syndrome, but there was no material left to confirm this diagnosis. These observations emphasize that penicillamine nephropathy, although usually reversible, may occasionally be progressive and life-threatening. Skin and appendages Bullous eruptions induced by penicillamine (SED-10, 413) with the characteristic features of pemphigus erythematosus, -foliaceus, -vulgaris, or of pemphigoid, continue to be reported (29-38cR). In this sequence the level of blister formation descends from the superficial layers of the epidermis to the subepidermal tissue. Pemphigus developed in 4 of 259 patients on penicillamine for systemic sclerosis (100. The condition may be serious and can even run a fatal course (32c, 37c). Treatment with plasmapheresis has been successful (28c). The eruption may start with localized itching and scaling patches, resembling seborrheic dermatitis. The patient described by Bahmer et al (29c) had at the same time features of pemphigus, bullous eruption and seborrheic dermatitis. The patient described in a report from the Netherlands had combined features of pemphigus and pemphigoid, though the rash had started with non-specific erytbemato-urticarial papules, urticarial plaques and painful buccal erosions; intact blisters were never observed (Mot). This interand even intra-individual pluriformity of penicillamine-induced bullous eruptions suggests some slight differences in the pathogenetic processes rather than the existence of a variety of essentially different reactions. The precise pathogenesis of penicillamine-induced pemphigus has, in spite of several fascinating hypotheses (29-36), largely remained unexplained. A fine paper by Shuttleworth et al, confirming the much older report by Pegum and Pembroke from 1977 (SEDA-2, 216), on 3 patients with cicatricial pemphigoid associated with the use of penicillamine, underlines the importance of the scarring and subsequent deformations that may ensue (36cR). In such patients, involvement of the conjunctiva and esophagus may cause symblepharon and stenosis of the pharynx or esophagus. One further case of cicatricial pemphigoid has been presented by Peyri et al (38~ A small number of articles have so far described the peculiar skin disorders that may be caused by the 'lathyrogenic' effect of high doses of penicillamine on collagen and elastic fibers in the skin (SED-10,413). Meyrick Thomas and Kirby recently provided details of
214 a patient who at the same time had elastosis perforans serpiginosa and the very rarely described pseudoxanthoma elasticum-like lesions (SEDA-9, 220), following the use of 2.25 g penicillamine daily for cystinuria (39cR). Two further reports described lichen planuslike eruptions in patients on penicillamine, involving the skin and the oral epithelium (40cR; 41cR). Genital The eighth case has been described of massive enlargement of the breasts in a woman on penicillamine (42cR). As the authors point out, parenchymal breast tissue (alveoli, lobules, ducts) is dependent upon estrogen and progestagen hormones for growth and development, whereas the connective tissue stroma is under the regulatory control of the pituitary gonadotrophins, prolactin and growth hormone. In the 3 cases where a tissue sample was examined, an increase in connective tissue was found with no change in glandular tissue. Serum prolactin was increased in 2 patients, but was normal in another subject. Several of the women with breast enlargement were postmenopausal. Although not fully understood, penicillamine-induced breast enlargement is presumably associated with a disturbance of prolactin or gonadotrophin metabolism. Four of the patients have successfully been treated with danazol. Endocrine Since their previous report on 1 patient (SEDA-10,219), Benson et al have described 2 further patients with penicillamineassociated anti-insulin antibodies, with symptomatic hypoglycemia in 1 (43CR). (The occurrence of hypo- rather than hyperglycemia in cases with anti-insulin antibodies is not fully understood but well known in patients with 'autoimmune hypoglycemia' (44r)). The antibody level fell sharply in both patients after penicillamine was discontinued. Since these 2 patients belonged to a series of 31 rheumatic patients on penicillamine, anti-insulin antibodies may perhaps be less rare than the small number of reported cases would suggest. A report from Denmark has described 2 patients with diabetes mellitus well controlled with insulin, who experienced hypoglycemic episodes 6 and 8 weeks after penicillamine had been started (45cr). The diabetes could subsequently be controlled with lower doses of insulin. No reference is made to the presence of anti-insulin antibodies in this patient. Musculoskeletal D'Anglejan et al were able to collect information on no fewer than 23
Chapter 24 R.H.B. Meyboom and LA. Jaffe original patients with penicillamine-associated
myasthenia (46cR). Presumably these cases were found in a series of 2100 patients on penicillamine, but the source is not entirely clear from the article. A calculated prevalence of myasthenia of 1%0 in patients on penicillamine would be within the range previously calculated (SEDA-5, 249; SEDA-7, 260). A similar prevalence of myasthenia occurred in the series of Steen et al: 1.5% (4 cases) in 259 patients, receiving penicillamine for systemic sclerosis (10c). It may be concluded that the penicillamine-induced form of myasthenia does not really differ clinically from genuine myasthenia gravis, except of course for the fact that most patients recover once penicillamine is stopped. Noteworthy was the predominance of mild cases, often only involving the eye muscles. As compared with spontaneous myasthenia, there was a deafly increased frequency of concomitantly occurring antinuclear antibodies. This observation, together with the association with different HLA antigens (SEDA-8, 235), may counter the view that one is dealing with spontaneous myasthenia gravis, occurring by pure coincidence in such cases. Devogelaer et al presented information on 3 further patients with myasthenia gravis and 1 with polymyositis, associated with the use of penicillamine (47CR). Other recent reports on penicillamine-induced polymyositis come from Sweden (48ca) and Portugal (49cR). Interestingly, in 2 patients (47, 48) there was some suspicion of a possibly pre-existing non-symptomatic myositis. RELATED DRUGS Pyritinol (SED-IO, 416) Especially in France, the sulfhydryl compound pyritinol (the dimer of 5-thiopyridoxine) is used as an alternative to penicillamine. In the usual doses, 600-800 mg daily, this drug has a profile of side effects similar to that of penicillamine (7R, 50R). Some 40% of the users experience adverse effects, leading to withdrawal in about 23% (of the total). Most frequent are non-specific rashes and stomatitis; in addition pemphigus, lichen planus and photosensitivity have occurred. Other complications of interest are hematological reactions (thrombocytopenia, agranulocytosis), myasthenia, nephrosis and polymyositis. Disturbances of taste may occur, but are less frequent than with penicillamine. A valuable confirmation of the
215
Metal antagonists Chapter 24 occurrence of such complications has been the collaborative study by French monitoring centers, listing 4 cases of pemphigus, 3 of agranulocytosis (but other drugs taken were oxyphenbutazone or clomipramine), 2 of nephrosis and (not previously described) 2 of a lupus syndrome, among 23 case-reports of suspected adverse reactions to pyritinol (9CR).
Tiopronin (N-(2-mercaptopropionyl)glycine) This other alternative to penicillamine used in rheumatoid arthritis and cystinuria, again has a pattern of adverse reactions resembling that ofpenicillamine (7R, 51R): 15% of the users experienced skin eruptions, necessitating withdrawal in 9% (rashes, stomatitis, lichen planus, alopecia); several cases of pemphigus are on record (SEDA-10, 223); proteinuria occurred in 12% of the users and occasionally deteriorated towards a nephrotic syndrome; 9% of the patients had abnormal taste. Thrombocytopenia may occur, but in the 2 cases with seriously impaired myelopoiesis reported so far, a relation with tiopronin was doubtful (51r).
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine This new sulfhydryl compound, also referred to as 'SA-96', has been tested in 11 patients with rheumatoid arthritis. Even in this small series hepatitis developed in 2 patients (52c). OTHER M E T A L A N T A G O N I S T S
Deferoxamine (desferrioxamine)
tials. Thirteen patients had high-frequency sensorineural hearing loss and 9 others had similar audiometric abnormalities without subjective hearing loss. Patients with side effects were found to be younger, to have lower serum ferritin values, and to have received higher doses of deferoxamine. The mechanism of toxicity has remained uncertain. Serial audiovisual monitoring is recommended, as is tailoring of the daily dose of deferoxamine with adjustment to the iron burden (as reflected by the serum ferritin levels and 24-hour iron excretion). A deferoxamine dose of 50 mg/kg would appear to be safe. The first report has been published o f a patient with thrombocytopenia, probably induced by deferoxamine (54c). A 57-year-old man with uremia had been treated with regular hemodialysis for 4 years. For subsequent aluminum storage and osteomalacia, deferoxamine was started (6 g added to the venous blood during the final hour of dialysis). In 2 months' time the number of platelets decreased to 45x 109/1. Purpura or splenomegaly were not evident. Bone marrow examination disclosed normal megakaryocytopoiesis. Deferoxamine was withheld after the 5th infusion and in the next 2 months the number of platelets returned to normal. Afterwards deferoxamine was on 2 occasions resumed and both times followed by a reversible relapse of thrombocytopenia. The authors pointed out that deferoxamine might accumulate in the event of renal failure if repeated doses are given. It may be prudent to monitor the platelet counts in hemodialysis patients who receive deferoxamine.
(SED-IO, 416; SEDA-8, 239; SEDA-9, 224; SEDA-IO, 223)
Deferoxamine and yersiniosis In SEDA-10, the first reports were reviewed of impaired vision and hearing induced by deferoxamine, and the development of unconsciousness in patients simultaneous receiving deferoxamine and a phenothiazine derivative. The neurotoxicity of deferoxamine has now been confirmed in a prospective study on 89 patients (age range 3-27 years) on a transfusion chelation program for fl-thalassemia (53cR). Deferoxamine was administered in dosages of 34-150 mg/kg by subcutaneous infusion over a 12-hour period each night. A total of 27 patients had symptoms or signs of neurotoxicity. Four patients had visual loss and optic neuropathy, 5 patients had asymptomatic changes in the pigment of the retina; 24 patients had abnormal visual-evoked poten-
Yersinia species ( Y. enterocolitica, Y. pseudotuberculosis) are gram-negative, aerobic and facultative anaerobic, non-spore-forming bacteria. They require iron but do not possess siderophores and therefore have limited virulence (55~). Yersinia bacteria predominantly produce enteric infections, usually diarrhea associated with adenitis and ileitis, and are also associated with the development of reactive arthritis and erythema nodosum. It has been known for some time that the virulence of Yersinia increases in the presence of excess iron and that lifethreatening systemic infection may occur (56). Iron overload has been found to be associated with impaired phagocytic activity of granulocytes (57cR).
216
In the past f e w years a number o f reports have provided evidence that the administration o f deferoxamine (which itself is a siderophore) facilitates - even in the absence o f iron storage disorders - the growth o f Yersinia bacteria and is associated with the risk o f septicemia, which has a high mortality (55 c~, 58-62ca ). Since the use o f deferoxamine nowadays extends to aluminium overload in hemodialysis, the population at risk for life-threatening systemic yersiniosis is considerably increased. The possibility o f Yersinia septicemia should be considered in any patient receiving deferoxamine who develops a febrile illness. The bacteria will grow on routine blood culture media, but identification can be difficult. Yersinia species are resistant to most antibiotics. I f treatment is needed before culture results are available, chloramphenicol or co-trimoxazole ( Y. enterocolitica ) and an aminoglycoside ( Y. pseudotuberculosis) should be administered (55) and deferoxamine discontinued.
Chapter 24 R.H.B. Meyboom and LA. Jaffe Edetic acid (SEDA-IO, 225) and pentetie acid
A zinc deficiency syndrome, with a papular, pustular and erosive rash o f the face and perianally, leukokeratosis of the tongue and stomatitis, developed in a patient on chelation treatment for manganese poisoning (63CR). The patient had received intravenous calcium trisodium edetate for 3 days (the a m o u n t is not stated) and calcium trisodium pentetate (2 g daily) for the following 11 days. The serum zinc level was f o u n d to be 40 lag/100ml (normal 58-100 lag/100 ml). The issue of chelation treatment for atherosclerosis has within the last year been addressed by Magee in Australia (63R). A case developing fatal renal tubular necrosis was described and the dangers and lack of efficacy of this procedure emphasized. Further reports on pseudo-thrombocytopenia caused by edetate (SEDA-10, 225) are to be found in the recent Spanish literature (65c-68c).
REFERENCES 1. Proceedings of the VIII French Conference of Rheumatology, Paris, 1985. Rev. Rhum., 1986, 53, 1. 2. Camus JP, Koeger AC, Laveant C, Leca AP (1986) P6nicillamine 1985. Rev. Rhum., 53, 1. 3. Valat JP, Fouquet B, Evenleigh MC et al (1986) La d-p6nicillamine dans le traitement de la polyarthrite rhumatoide. Rev. Rhum., 53, 7. 4. Howard-Lock HE, Lock CJL, Mewa A, Kean W (1986) D-Penicillamine: chemistry and clinical use in rheumatoid arthritis. Semin. Arthritis Rheum., 15, 261. 5. Hurst NP, Bell AL, Nuki G (1986) Studies of the effect of d-penicillamlne and sodium aurothiomalate therapy on superoxide anion production by monocytes from patients with reumatoid arthritis: evidence for in vivo stimulation of monocytes. Ann. Rheum. Dis., 45, 37. 6. Smite ND, Messner RP, Zoschke DC 0985) In vitro production and scavenging of hydrogen peroxide by D-penicillamine. Arthritis Rheum., 28, 914. 7. Jaffe IA (1986) Adverse effects profile of sulphydryl compounds in man. Am. J. Med., 80, 471. 8. Camus JP, Koeger AC, Struz P, Laveant C (1986) Traitements de fond sulfhydryl6s au cours de la polyarthrite rhumatoide. Rev. Rhum., 53, 31. 9. Netter P, Trechot P, Bannwarth B et al (1985) Effets secondaires de la D-p~nicillamine et du pyritinol. Thbrapie, 40, 475. I0. Stcen VD, Blair S, Medsger A (1986) The toxicity of d-penicillamine in systemic sclerosis. Ann. Intern. Med., 104, 699.
11. Neuberger J, Christensen E, Portmann B e t al (1985) Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis. Gut, 26, 114. 12. Dickson ER, Fleming TR, Wiesner RH et al (1985) Trial of penicillamine in advanced primary biliary cirrhosis. N. Engl. J. Med., 312, 1011. 13. Steven MM, Morrison M, Sturrock RD (1985) Pencillamine in anky|osing spondylitis: a double blind placebo controlled trial. J. Rheumatol., 12, 735. 14. Bardin ~, Dryll A, Ryckewaert A (1986) Syst6me HLA et accidents du traitement de la polyarthrite rhumatoide par la d-p6nicillamine. Rev. Rhum., 53, 27. 15. Perrier P, Raffoux C, Thomas P et al (1985) HLA antigens and toxic reactions to sodium aurothiopropanol-sulphonate and d-penicillamine in patients with rheumatoid arthritis. Ann. Rheum. Dis.. 44, 621. 16. Speerstra F, Reekers P, Van de Putte LBA, Vandenbroucke JP (1985) HLA associations in aurothioglucose- and d-penicillamine-induced haematotoxic reactions in rheumatoid arthritis. Tissue Antigens, 26, 35. 17. Renier JC, Bontoux-Carre E, Racineux JL (1986) Trois observations de bronchiolite oblit&ante lors du traitement de ta polyarthrite rhumato/de par la d-p6nicillamine. Rev. Rhum., 53, 25. 18. Bontoux-Carr6 E, Renier JC, Racineux JL (1985) Les bronchiolites oblit6rantes induites par la d-p6nicillamine lors du traitement de la polyarthrite rhumatoide. Sem. H@., 61, 3055. 19. Hayashi S, Hirose N, Ikeda T, Shigematsu N
Metal antagonists
Chapter 24
(1985) A case of prolonged pulmonary eosinophilia caused by d-penicillamine. Nippon Kyobu Shikkan Gakkai Zasshi, 23, 479. 20. Kumar A, Bhat A, Gupta DK et al (1985) DPenicillamine-induced acute hypersensitivity pneumonitis and cholestatic hepatitis in a patient with rheumatoid arthritis. Clin. Exp. Rheumatol., 3, 337. 21. Henzgen M, Hein G (1985) Agranulozytose und andere Nebenwirkungen: Erfahrungen met der D-Penicillamintherapie bei der Rheumatoidarthritis. Z. Klin. Med., 40, 521. 22. Umeki S, Konishi Y, Yasuda T et al (1985) DPeniciltamine and neutrophilic agranulocytosis. Arch. Intern. Med., 145, 2271. 23. Sheldon P, Wood JK (1985) Remission of arthritis and radiological improvement after combination therapy for non-Hodg~in's lymphoma in a patient with rheumatoid arthritis undergoing treatment with d-penicillamine. ~nn. Rheum. Dis., 44, 556. 24. Gefel D, Harats N, Lijovetsky G, Eliakim M (1985) Cholestatic jaundice associated with dpenicillamine therapy. Scand. J. Rheumatol., 14, 303. 25. Stein HB, Schroeder ML, Dillon AM (1986) Peniclllamine-induced proteinuria: risk factors. Semin. Arthritis Rheum., 15, 282. 26. Rehan A, Johnson K (1986) IgM nephropathy associated with penicillamine. Am. J. Nephrol., 6, 71. 27. Sadjadi SA, Seelig MS, Berger AR, Milstoc M (1985) Rapidly progressive glomerulonephritis in a patient with rheumatoid arthriti~ during treatment with high-dosage d-penicillamine. Am. J. Nephrol., 5, 212. 28. WiUians AJ, Fordham JN, Barnes CG, Goodwin FJ (1986) Progressive proliferative glomerulonephritis in a patient with rheumatoid arthritis treated with d-penicillamine. Ann. Rheum. Dis., 45, 82. 29. Bahmer FA, Bambauer R, Stenger D (1985) Penicillamine-induced pemphigus foliaceus-like dermatosis. Arch. Dermatol., 121, 665. 30. Gibson LE, Dicken CH (1985) Pemphigus erythematosus, primary biliary cirrhosis, and dpenicillamine: report of a case. J. Am. Acad. Dermatol., 12, 883. 31. Ho VC, Stein HB, Ongley RC, Mcleod WA (1985) Penicillamine induced pemphigus. J. Rheumatol., 12, 583. 32. Piette-Brion B, De Bast C, Chamoun E et al (1985) Pemphigus superficiel apparu lors du traitement d'une polyarthrite rhumatoide par d-p6nicillamine et piroxicam. Dermatologica, 170, 297. 33. Gall Y, Guillet G, Leroy JP et al (1986) Bulles et 16sions urticariformes de vascularit6 allergique avec immunomarquage de type pemphigoide bulteuse lors d'un traitement par d-p6nicillamine. Ann. Dermatol. V~n~r~ol., 113, 55, 34. Velthuis PJ, Hendrikse JC, Nefkens JJ (1985) Combined features of pemphigus and pemphigoid induced by penicillamine. Br. J. Dermatol., 112, 615.
217 35. Stiegleder GK (1985) Penicillamin und Blasenbildung. Z. Hautkr., 21, 1653. 36. Shuttleworth D, Graham-Brown RA, Hutchinson PE, Jolliffe DS (1985) Cicatricial pemphigoid in d-penicillamine treated patients with rheumatoid arthritis: a report of three cases. Clin. Exp. Dermatol., 10, 392. 37. Kohn SR (1986) Fatal penicillamine-induced pemphigus foliaceus-like dermatosis. Arch. DermatoL, 122, 17. 38. Peyri J, Servitje O, Ribera M e t al (1986) Cicatricial pemphigoid in a patient with rheumatoid arthritis treated with d-penicillamine. J. Am. Acad. DermatoL, 14, 681. 39. Meyrick Thomas RH, Kirby JDT (1985) Elastosis perforans serpiginosa and pseudoxanthoma elasticum-like skin change due to d-penicillamine. Clin. Exp. Dermatol., 10, 386. 40. Floreani A, Chiaramonte M, Pagnes P et al (1984) Lichen planus da penicillamina in paziente con cirrose biliare primitiva. Eur. Rev. Med. PharmacoL Sci., 6, 481. 41. Weismann K, Wantzin GL, Christensen E (1986) Lichen planus red peniciUaminbchandlet primaer biliaer cirrose. Ugeskr. Laeg., 148, 456. 42. Kahl LE, Medsger TA, Klein I (1985) Massive breast enlargement in a patient receiving dpenicillamine for systemic sclerosis. J. RheumatoL, 12, 990. 43. Benson EA, Healy LA, Barron EI (1985) Insulin antibodies in patients receiving penicillamine. Am. J. Meal., 78, 857. 44. Becker RC, Martin R (1986) Penicillamineinduced insulin antibodies. Ann. Intern. Med., 104, 128. 45. Elling P, Elling H (1985) Penicillamine, captopill and hypoglycemia. Ann. Intern. Med., 103, 644. 46. D'Anglejan J, Morel E, Feuillet-Fieux MN et al (1985) Myasthtnie induite par la d-penicillamine. Presse Mbd., 14, 2336. 47. Devogelaer JP, Isaac G, Notl H e t al (1985) Neuromuscular disorders associated with d-penicillamine treatment for rheumatoid arthritis. Int. J. Clin. Pharmacol. Res., 5, 143. 48. Leden I, Libelius R (1985) Penicillamineinduced polymyositis. Scand. J. Rheumatol., 14, 90. 49. Rosa CM, Queiroz MV (1985) Um caso de polimiosite induzida pela d-penicilamina. Acta Reumatol. Port., 10, 141. 50. Crouzet J, Beraneck L (1986) Pyrithioxine et polyarthrite rhumatoide. Rev. Rhum., 53, 45. 51. Amor B, Mery C, De Gery A, Zizi M (1986) Tiopronine r polyarthrite rhumatoide. Rev. Rhum., 53, 39. 52. Ishikawa K, Sakaguchi M (1986) SA 96 (N-(2Mercapto-2-methylpropanoyl)-L-cysteine) in rheumatoid arthritis. Scand. J. Rheumatol., 15, 85. 53. Olivieri NF, Buncic JR, Chew E (1986) Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N. Engl. J. Med., 314, 869. 54. Walker JA, Sherman RA, Eisinger RP (1985)
218 Thrombocytopenia associated with intravenous desferrioxamine. Am. J. Kidney Dis., 6, 254. 55. Boyce N, Wood C, Holdsworth S e t al (1985) Life-threatening sepsis complicating heavy metal chelation therapy with desferrioxamine. Aust. N Z J. Med., 15, 654. 56. Melby K, Slordahl S, Gutteberg T J, Nordbo SA (1982) Septicaemia due to Yersinia enterocolitica after oral overdoses of iron. Br. Med. J., 285, 467. 57. Waterlot Y, Caninieaux B, Hariga-Muller C (1985) Impaired phagocytic activity 'of neutrophil in patients receiving haemodialysis: the critical role of iron overload. Br. Med. J., 291, 501. 58. Robins-Browne RM, Prpic JK (1983) Desferrioxamine and systemic yersiniosis. Lancet, 2, 1372. 59. Scharnetzky M, K6nig R, Lakomek M e t al 0984) Prophylaxis of systemic yersiniosis in thalassaemia major. Lancet, 1, 791. 60. Waterlot Y, Vanherweghem J-L (1985) Desferrioxamine en h6modialyse fi l'origine d'une septic6mie ~ Yersinia enterocolitica. Presse M$d., 14, 699. 61. Chiu HY, Flynn DM, Hoffbrand AV, Politis D
Chapter 24
R.H.B. Meyboom and LA. Jaffe
(1986) Infections with Yersinia enterocolitica in patients with iron overload. Br. Med. J., 292, 97. 62. Kelly D, Price E, Wright Vet al (1986) Yersinia and iron overload. Br. Med. J., 292, 413. 63. Proksch E, K61mel K (1985) Zinkmangelsyndrom als Nebenwirkung von Chelatbildern. Dtsch. Med. Wocher~chr., 110, 1001. 64. Magee R (1985) Chelation treatment of atherosclerosis. Med. J. ,,lust., 142, 514. 65. Casals FJ, Alfonso L, Alonso A e t al (1985) Seudotrombocitopenia como causa de diagnostico erroneo de la enfermedad de Werlhof. Med. Clin. Barcelona, 84, 721. 66. Feliu E, Gardella S (1985) Seudotrombocitopenia por extraction de sangre con acido etilendiamino-tetraacctico (EDTA): un causa de error diagnostico. Med. Clin. Barcelona, 84, 738. 67. Grau Segura E, Fontcuberta Boj J, Felez Brugues J (1985) Seudotrombocitopenia y seudoleucocitosis. Med. Clin. Barcelona, 84, 754. 68. GardeUa S, Feliu E, Labal F et al (1985) Seudotrombocitopenia pot EDTA" posible causa de un diagnostico erroneo de enfermedad de Werlhof. Med. Clin. Barcelona, 84, 755.
24 PeniciUamine (SED-IO,409; SEDA-8, 235; SEDA-9, 223; SEDA-IO, 217) General Under the title Pbnicillamine, bilan d'une expbrience, the second part of the VIII French Conference of Rheumatology (Paris, 19-20 March, 1985) was devoted to peniciUamine (lCX). Camus et al on that occasion reviewed the history and the use of penicillamine in human disease (2R). Valat et al presented the results of a 5-year follow-up study on 104 patients receiving penicillamine for rheumatoid arthritis. Their findings confirm those of earlier studies, that penicillamine is effective in rheumatoid arthritis but that its use is limited by frequent side effects and relapses of the disease (3CR). After 5 years, only 26% of the patients were still taking penicillamine with satisfactory results, 45% had stopped the drug because of side effects and 14.5% did so because of insufficient effect (the remaining 14.5% withdrew from follow-up). Withdr~awal due to side effects largely occurred during the first 2 years of the treatment and rarely thereafter. Predominant side effects were, in decreasing frequency, proteinuria, skin reactions, and blood dyscrasias. A welcome up-to-date overview of the chemistry, kinetics and the complex pharmacology of penicillamine has been provided by Howard-Lock et al (4~). Penicillamine has 3 major biochemical effects: (a) The formation of disulfide links with other sulfhydryl compounds, as the result of either an oxidation or an exchange reaction. This effect is successfully applied in the treatment of cystinuria. (b) Condensation with carbonyl compounds (aldehydes and ketones) to give substituted thiazolidine carboxylic acids, causing inhibition of collagen cross-linking. This property is responsible for the 'lathyrogenic' effect on the skin of high doses of penicillamine, and is experimentally used in the treatment of scleroderma and fibrotic disorders and for acetaldehyde detoxification. (c) Formation of complexes or chelates with metals. Firstly, this effect is used in the treatment of metal Side Effects of Drugs Annual 11 M.N.G. Dukes,editor 9 ElsevierSciencePublishersB.V., 1987
Metal antagonists poisoning and of Wilson's diseasr Secondly, complexes with trace metals (copper) may interfere with enzymatic processes (e.g. with superoxide dismutase) and may influence the production and scavenging of oxygen-derived free radicals and the process of inflammation. Recent work has provided further data on the effect of penicillamine, be it direct or indirect, on the production of superoxides (5cx, 6cR) and seems promising with regard to the unraveling of the influence o f this drug on rheumatoid arthritis and on immune processes. Jaffe has discussed the apparent similarity of the patterns of side effects of various sulfhydryl compounds (7R). In this light it is interesting that, in accordance with previous reports (SEDA-8, 236; SEDA-9, 223), it was found in a study of 10 years duration that the responses to a sulflaydryl drug (penicillamine, sodium aurothiomalate and aurothioglucose or pyritinol), either therapeutic or adverse, are - with the exception of proteinuria - largely independent of earlier experiences with one of the other drugs in this group (8cx). An interesting new approach to the study of the side effects of penicillamine is the collaborative study by regional 'pharmacovigilance' centers in France (9cR). Over a 4-year period, 78 reports were collected on suspected adverse reactions to penicillamine. There was a predominance of blood dyscrasias (23 cases), pemphigus-like eruptions (9 cases), nephrotic syndrome (5) and myasthenia (5 cases). Noteworthy too, are 2 cases of myositis and 1 of Goodpasture's syndrome. The 5 cases of 'pulmonary fibrosis', however, need further clarification. The emerging pattern of reactions is influenced by the fact that more severe reactions are more prone to be reported than are mild effects. The French study shows that certain complications of penicillamine ,which have only occasionally been described in the literature are in fact encountered in medical practice. Also interesting was the comparison in the French study with 23 case-reports on pyritinol (see below). A large trial with 259 patients has yielded a similar pattern of adverse reactions to penicillamine in patients with systemic sclerosis as
212 compared with rheumatoid arthritis (10cR). 47% of the patients had side effects and 29% of the patients had to stop the drug for this reason. Skin reactions, proteinuria, and thrombo- and leukopenia predominated. There were 4 patients with pemphigus and also 4 with myasthenia gravis, attributed to the use of penicillamine. Penicillamine has not been found effective in biliary cirrhosis (11 cR, 12eR) or ankylosing spondylitis (13oR). HLA antigens (SEDA-8, 235; SEDA-IO, 217) The association between HLA antigens and the occurrence of adverse reactions to penicillamine has been reviewed by Bardin et al (14R). The most important finding in this respect is that the antigens B8 and DR3 are associated with nephropathy. In another series of 141 patients receiving either gold or penicillamine, the relative risks of DR3-positive patients developing skin reactions or proteinuria were calculated to be 10.5 and 7 respectively as compared with DR3 negatives (15CR). The frequency of DR7 antigen in patients with side effects, on the other hand, was significantly decreased, suggesting a protective role for this antigen. Speerstra et al have found a strong association between antigens B8 and DR3 and the development of hematological reactions to aurothioglucose, but in the penicillamine group this association did not reach significance (16cR). By contrast, in the group of patients with hematological reactions to penicillamine there was an increased incidence of antigen DR4 (all patients with thrombocytopenia were DR4positive), and the authors concluded that the HLA phenotype contributing to an increased risk may be different for these 2 antirheumatic drugs (16cR). In summary, the study of HLA phentoypes in patients experiencing side effects with penicillamine is a very interesting scientific issue, but has little value for the monitoring of individual patients treated with this drug. The reader may like to compare this conclusion with that presented by Riel in Chapter 23 of this volume.
Respiratory tract Three further patients have been reported with severe and irreversible
bronchiolitis obliterans, developed within 4-8 months of treatment with penicillamine (in doses not exceeding 600mg daily) (17cR). As has been pointed out in SEDA-8 (p. 236), however, it is doubtful whether this association is causal. Another article (18) refers to the same patients.
Chapter 24 R.H.B. Meyboom and LA. Jaffe From Japan came a report on a patient with probably penicillamine-induced eosinophilic pneumonitis (19ca). Another case-report describes the simultaneous development of pneumonitis, hepatitis, rash, and fever after 10 days use of penicillamine (250 mg daily) (see 'Liver') (20cR). The causal relationship was established by a relapse on inadvertent re-exposure to penicillamine 5 months later.
Hematological
In a collaborative study of regional drug monitoring centers in France, hematological reactions (thrombocytopenia, granulocytopenia, and pancytopenia) predominated with altogether 22 cases in a total of 78 case-reports (9c). In another French series 9 of 104 patients experienced hematological reactions, including 2 patients with aplastic anemia, which ran a fatal course in 1 (3c). In a series of 259 patients with systemic sclerosis, the use of penicillamine was associated with thrombocytopenia in 10 and with leukopenia in 6 subjects (10r Henzgen and Hein had 2 patients with blood dyscrasias in their series of 34 patients (21"). One patient had agranulocytosis developing within 4 weeks' use of peniciiiamine 300 mg; the other patient had transient pancytopenia. Hematological side effects can appear quite rapidly. Umeki et al described the development of profound granulocytopenia with rash and fever in a 12-year-old girl, after only 7 days of treatment with penicillamine (800mg) for Wilson's disease (22CR). The role of penicillamine was demonstrated by the rapid recovery on withdrawal of penicillamine and a subsequent relapse of granulocytopenia after re-exposure to the drug."The lymphocyte transformation rate of lymphocyte cultures in the presence of penicillamine was 3 times higher than in lymphocytes that had not been exposed to penicillamine. This observation suggests that penicillamine-induced granulocytopenia is a delayed type hypersensitivity reaction. In conclusion, blood dyscrasias are relatively frequent complications to penicillamine, may develop suddenly, and are potentially lifethreatening. The development was described of a nonHodgkin's lymphoma in a patient with rheumatoid arthritis undergoing treatment with penicillamine, but no relationship was suspected (23c~). Interestingly, there was a remission of arthritis after chemotherapy for the lymphoma. Liver An excellent case-report illustrates the fact that cholestatic hepatitis, however rare, can
Metal antagonists Chapter24 occur as a complication to peniciUamine (24cR). The patient simultaneously had fever and a rash. The comprehensive case-report by Kumar et al is in several respects of interest (20ca). This patient, a 45-year-old woman, was admitted with fever, rash and severe dyspnea, developing 10 days after starting treatment with penicillamine and naproxen (250 and 1000mg daily, respectively) for rheumatoid arthritis. The chest X-ray showed bilateral fluffy shadows, and a diagnosis of acute hypersensitivity pneumonitis was made. Both drugs were discontinued and a short course of prednisone given. The respiratory symptoms rapidly disappeared, but fever and rash persisted for a few days and in addition cholestatic jaundice developed. No extrahepatic cause for the cholestasis was found. The patient recovered fully over a period of 4 weeks and was subsequently treated with naproxen alone without problems. An inadvertent re-exposure to penicillamine, however, was followed by a second attack of dyspnea and jaundice, providing the proof that penicillamine was the factor responsible. Urinary system Stein et al have now presented details of 26 patients with penicillamineassociatedproteinuria, i.e. 9% out of a series of 300 patients (25cR). In 10 patients proteinuria exceeded 3.5 g/24h. A nephrotic syndrome developed in 3 patients and hypertension in 1. Although 4 patients had a transient increase in serum creatinine, no renal in~atticiency occurred. Eight of the patients concomitantly had a skin rash. Proteinuria lasted for an average of 5.5 months but was reversible in all patients, despite continuation of penicillamine in 4 subjects. In 1 patient a renal biopsy was taken, revealing membranous glomerulonephritis with dense intramembranous deposits on electron microscopy, identified as IgG and C3 on immunofluorescent staining. This is the usual picture in such patients. Predisposing factors were previous gold nephropathy and the presence of HLA antigens DR3 and B8. An excellent case-report by Rehan and Johnson is unusual in that the predominant finding was deposition of IgM (instead of IgG) in the mesangial regions, i.e. the picture of the so-called IgM nephropathy or mesangial proliferative glomerulonephritis (26c~). In this patient, who had been taking only 250 mg penicillamine for 8 months, the rapid disappearance of proteinuria after stopping penicillamine was strongly suggestive of a causal involvement of the drug. In 2 recent reports, proliferative glomerulonephritis, presumably penicillamine-induced, had a fatal outcome (27cR, 28cR). In 1 case (27) a concomitant hemorrhagic pneumonitis was
213 suggestive of the presence of Goodpasture's syndrome, but there was no material left to confirm this diagnosis. These observations emphasize that penicillamine nephropathy, although usually reversible, may occasionally be progressive and life-threatening. Skin and appendages Bullous eruptions induced by penicillamine (SED-10, 413) with the characteristic features of pemphigus erythematosus, -foliaceus, -vulgaris, or of pemphigoid, continue to be reported (29-38cR). In this sequence the level of blister formation descends from the superficial layers of the epidermis to the subepidermal tissue. Pemphigus developed in 4 of 259 patients on penicillamine for systemic sclerosis (100. The condition may be serious and can even run a fatal course (32c, 37c). Treatment with plasmapheresis has been successful (28c). The eruption may start with localized itching and scaling patches, resembling seborrheic dermatitis. The patient described by Bahmer et al (29c) had at the same time features of pemphigus, bullous eruption and seborrheic dermatitis. The patient described in a report from the Netherlands had combined features of pemphigus and pemphigoid, though the rash had started with non-specific erytbemato-urticarial papules, urticarial plaques and painful buccal erosions; intact blisters were never observed (Mot). This interand even intra-individual pluriformity of penicillamine-induced bullous eruptions suggests some slight differences in the pathogenetic processes rather than the existence of a variety of essentially different reactions. The precise pathogenesis of penicillamine-induced pemphigus has, in spite of several fascinating hypotheses (29-36), largely remained unexplained. A fine paper by Shuttleworth et al, confirming the much older report by Pegum and Pembroke from 1977 (SEDA-2, 216), on 3 patients with cicatricial pemphigoid associated with the use of penicillamine, underlines the importance of the scarring and subsequent deformations that may ensue (36cR). In such patients, involvement of the conjunctiva and esophagus may cause symblepharon and stenosis of the pharynx or esophagus. One further case of cicatricial pemphigoid has been presented by Peyri et al (38~ A small number of articles have so far described the peculiar skin disorders that may be caused by the 'lathyrogenic' effect of high doses of penicillamine on collagen and elastic fibers in the skin (SED-10,413). Meyrick Thomas and Kirby recently provided details of
214 a patient who at the same time had elastosis perforans serpiginosa and the very rarely described pseudoxanthoma elasticum-like lesions (SEDA-9, 220), following the use of 2.25 g penicillamine daily for cystinuria (39cR). Two further reports described lichen planuslike eruptions in patients on penicillamine, involving the skin and the oral epithelium (40cR; 41cR). Genital The eighth case has been described of massive enlargement of the breasts in a woman on penicillamine (42cR). As the authors point out, parenchymal breast tissue (alveoli, lobules, ducts) is dependent upon estrogen and progestagen hormones for growth and development, whereas the connective tissue stroma is under the regulatory control of the pituitary gonadotrophins, prolactin and growth hormone. In the 3 cases where a tissue sample was examined, an increase in connective tissue was found with no change in glandular tissue. Serum prolactin was increased in 2 patients, but was normal in another subject. Several of the women with breast enlargement were postmenopausal. Although not fully understood, penicillamine-induced breast enlargement is presumably associated with a disturbance of prolactin or gonadotrophin metabolism. Four of the patients have successfully been treated with danazol. Endocrine Since their previous report on 1 patient (SEDA-10,219), Benson et al have described 2 further patients with penicillamineassociated anti-insulin antibodies, with symptomatic hypoglycemia in 1 (43CR). (The occurrence of hypo- rather than hyperglycemia in cases with anti-insulin antibodies is not fully understood but well known in patients with 'autoimmune hypoglycemia' (44r)). The antibody level fell sharply in both patients after penicillamine was discontinued. Since these 2 patients belonged to a series of 31 rheumatic patients on penicillamine, anti-insulin antibodies may perhaps be less rare than the small number of reported cases would suggest. A report from Denmark has described 2 patients with diabetes mellitus well controlled with insulin, who experienced hypoglycemic episodes 6 and 8 weeks after penicillamine had been started (45cr). The diabetes could subsequently be controlled with lower doses of insulin. No reference is made to the presence of anti-insulin antibodies in this patient. Musculoskeletal D'Anglejan et al were able to collect information on no fewer than 23
Chapter 24 R.H.B. Meyboom and LA. Jaffe original patients with penicillamine-associated
myasthenia (46cR). Presumably these cases were found in a series of 2100 patients on penicillamine, but the source is not entirely clear from the article. A calculated prevalence of myasthenia of 1%0 in patients on penicillamine would be within the range previously calculated (SEDA-5, 249; SEDA-7, 260). A similar prevalence of myasthenia occurred in the series of Steen et al: 1.5% (4 cases) in 259 patients, receiving penicillamine for systemic sclerosis (10c). It may be concluded that the penicillamine-induced form of myasthenia does not really differ clinically from genuine myasthenia gravis, except of course for the fact that most patients recover once penicillamine is stopped. Noteworthy was the predominance of mild cases, often only involving the eye muscles. As compared with spontaneous myasthenia, there was a deafly increased frequency of concomitantly occurring antinuclear antibodies. This observation, together with the association with different HLA antigens (SEDA-8, 235), may counter the view that one is dealing with spontaneous myasthenia gravis, occurring by pure coincidence in such cases. Devogelaer et al presented information on 3 further patients with myasthenia gravis and 1 with polymyositis, associated with the use of penicillamine (47CR). Other recent reports on penicillamine-induced polymyositis come from Sweden (48ca) and Portugal (49cR). Interestingly, in 2 patients (47, 48) there was some suspicion of a possibly pre-existing non-symptomatic myositis. RELATED DRUGS Pyritinol (SED-IO, 416) Especially in France, the sulfhydryl compound pyritinol (the dimer of 5-thiopyridoxine) is used as an alternative to penicillamine. In the usual doses, 600-800 mg daily, this drug has a profile of side effects similar to that of penicillamine (7R, 50R). Some 40% of the users experience adverse effects, leading to withdrawal in about 23% (of the total). Most frequent are non-specific rashes and stomatitis; in addition pemphigus, lichen planus and photosensitivity have occurred. Other complications of interest are hematological reactions (thrombocytopenia, agranulocytosis), myasthenia, nephrosis and polymyositis. Disturbances of taste may occur, but are less frequent than with penicillamine. A valuable confirmation of the
215
Metal antagonists Chapter 24 occurrence of such complications has been the collaborative study by French monitoring centers, listing 4 cases of pemphigus, 3 of agranulocytosis (but other drugs taken were oxyphenbutazone or clomipramine), 2 of nephrosis and (not previously described) 2 of a lupus syndrome, among 23 case-reports of suspected adverse reactions to pyritinol (9CR).
Tiopronin (N-(2-mercaptopropionyl)glycine) This other alternative to penicillamine used in rheumatoid arthritis and cystinuria, again has a pattern of adverse reactions resembling that ofpenicillamine (7R, 51R): 15% of the users experienced skin eruptions, necessitating withdrawal in 9% (rashes, stomatitis, lichen planus, alopecia); several cases of pemphigus are on record (SEDA-10, 223); proteinuria occurred in 12% of the users and occasionally deteriorated towards a nephrotic syndrome; 9% of the patients had abnormal taste. Thrombocytopenia may occur, but in the 2 cases with seriously impaired myelopoiesis reported so far, a relation with tiopronin was doubtful (51r).
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine This new sulfhydryl compound, also referred to as 'SA-96', has been tested in 11 patients with rheumatoid arthritis. Even in this small series hepatitis developed in 2 patients (52c). OTHER M E T A L A N T A G O N I S T S
Deferoxamine (desferrioxamine)
tials. Thirteen patients had high-frequency sensorineural hearing loss and 9 others had similar audiometric abnormalities without subjective hearing loss. Patients with side effects were found to be younger, to have lower serum ferritin values, and to have received higher doses of deferoxamine. The mechanism of toxicity has remained uncertain. Serial audiovisual monitoring is recommended, as is tailoring of the daily dose of deferoxamine with adjustment to the iron burden (as reflected by the serum ferritin levels and 24-hour iron excretion). A deferoxamine dose of 50 mg/kg would appear to be safe. The first report has been published o f a patient with thrombocytopenia, probably induced by deferoxamine (54c). A 57-year-old man with uremia had been treated with regular hemodialysis for 4 years. For subsequent aluminum storage and osteomalacia, deferoxamine was started (6 g added to the venous blood during the final hour of dialysis). In 2 months' time the number of platelets decreased to 45x 109/1. Purpura or splenomegaly were not evident. Bone marrow examination disclosed normal megakaryocytopoiesis. Deferoxamine was withheld after the 5th infusion and in the next 2 months the number of platelets returned to normal. Afterwards deferoxamine was on 2 occasions resumed and both times followed by a reversible relapse of thrombocytopenia. The authors pointed out that deferoxamine might accumulate in the event of renal failure if repeated doses are given. It may be prudent to monitor the platelet counts in hemodialysis patients who receive deferoxamine.
(SED-IO, 416; SEDA-8, 239; SEDA-9, 224; SEDA-IO, 223)
Deferoxamine and yersiniosis In SEDA-10, the first reports were reviewed of impaired vision and hearing induced by deferoxamine, and the development of unconsciousness in patients simultaneous receiving deferoxamine and a phenothiazine derivative. The neurotoxicity of deferoxamine has now been confirmed in a prospective study on 89 patients (age range 3-27 years) on a transfusion chelation program for fl-thalassemia (53cR). Deferoxamine was administered in dosages of 34-150 mg/kg by subcutaneous infusion over a 12-hour period each night. A total of 27 patients had symptoms or signs of neurotoxicity. Four patients had visual loss and optic neuropathy, 5 patients had asymptomatic changes in the pigment of the retina; 24 patients had abnormal visual-evoked poten-
Yersinia species ( Y. enterocolitica, Y. pseudotuberculosis) are gram-negative, aerobic and facultative anaerobic, non-spore-forming bacteria. They require iron but do not possess siderophores and therefore have limited virulence (55~). Yersinia bacteria predominantly produce enteric infections, usually diarrhea associated with adenitis and ileitis, and are also associated with the development of reactive arthritis and erythema nodosum. It has been known for some time that the virulence of Yersinia increases in the presence of excess iron and that lifethreatening systemic infection may occur (56). Iron overload has been found to be associated with impaired phagocytic activity of granulocytes (57cR).
216
In the past f e w years a number o f reports have provided evidence that the administration o f deferoxamine (which itself is a siderophore) facilitates - even in the absence o f iron storage disorders - the growth o f Yersinia bacteria and is associated with the risk o f septicemia, which has a high mortality (55 c~, 58-62ca ). Since the use o f deferoxamine nowadays extends to aluminium overload in hemodialysis, the population at risk for life-threatening systemic yersiniosis is considerably increased. The possibility o f Yersinia septicemia should be considered in any patient receiving deferoxamine who develops a febrile illness. The bacteria will grow on routine blood culture media, but identification can be difficult. Yersinia species are resistant to most antibiotics. I f treatment is needed before culture results are available, chloramphenicol or co-trimoxazole ( Y. enterocolitica ) and an aminoglycoside ( Y. pseudotuberculosis) should be administered (55) and deferoxamine discontinued.
Chapter 24 R.H.B. Meyboom and LA. Jaffe Edetic acid (SEDA-IO, 225) and pentetie acid
A zinc deficiency syndrome, with a papular, pustular and erosive rash o f the face and perianally, leukokeratosis of the tongue and stomatitis, developed in a patient on chelation treatment for manganese poisoning (63CR). The patient had received intravenous calcium trisodium edetate for 3 days (the a m o u n t is not stated) and calcium trisodium pentetate (2 g daily) for the following 11 days. The serum zinc level was f o u n d to be 40 lag/100ml (normal 58-100 lag/100 ml). The issue of chelation treatment for atherosclerosis has within the last year been addressed by Magee in Australia (63R). A case developing fatal renal tubular necrosis was described and the dangers and lack of efficacy of this procedure emphasized. Further reports on pseudo-thrombocytopenia caused by edetate (SEDA-10, 225) are to be found in the recent Spanish literature (65c-68c).
REFERENCES 1. Proceedings of the VIII French Conference of Rheumatology, Paris, 1985. Rev. Rhum., 1986, 53, 1. 2. Camus JP, Koeger AC, Laveant C, Leca AP (1986) P6nicillamine 1985. Rev. Rhum., 53, 1. 3. Valat JP, Fouquet B, Evenleigh MC et al (1986) La d-p6nicillamine dans le traitement de la polyarthrite rhumatoide. Rev. Rhum., 53, 7. 4. Howard-Lock HE, Lock CJL, Mewa A, Kean W (1986) D-Penicillamine: chemistry and clinical use in rheumatoid arthritis. Semin. Arthritis Rheum., 15, 261. 5. Hurst NP, Bell AL, Nuki G (1986) Studies of the effect of d-penicillamlne and sodium aurothiomalate therapy on superoxide anion production by monocytes from patients with reumatoid arthritis: evidence for in vivo stimulation of monocytes. Ann. Rheum. Dis., 45, 37. 6. Smite ND, Messner RP, Zoschke DC 0985) In vitro production and scavenging of hydrogen peroxide by D-penicillamine. Arthritis Rheum., 28, 914. 7. Jaffe IA (1986) Adverse effects profile of sulphydryl compounds in man. Am. J. Med., 80, 471. 8. Camus JP, Koeger AC, Struz P, Laveant C (1986) Traitements de fond sulfhydryl6s au cours de la polyarthrite rhumatoide. Rev. Rhum., 53, 31. 9. Netter P, Trechot P, Bannwarth B et al (1985) Effets secondaires de la D-p~nicillamine et du pyritinol. Thbrapie, 40, 475. I0. Stcen VD, Blair S, Medsger A (1986) The toxicity of d-penicillamine in systemic sclerosis. Ann. Intern. Med., 104, 699.
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Metal antagonists
Chapter 24
(1985) A case of prolonged pulmonary eosinophilia caused by d-penicillamine. Nippon Kyobu Shikkan Gakkai Zasshi, 23, 479. 20. Kumar A, Bhat A, Gupta DK et al (1985) DPenicillamine-induced acute hypersensitivity pneumonitis and cholestatic hepatitis in a patient with rheumatoid arthritis. Clin. Exp. Rheumatol., 3, 337. 21. Henzgen M, Hein G (1985) Agranulozytose und andere Nebenwirkungen: Erfahrungen met der D-Penicillamintherapie bei der Rheumatoidarthritis. Z. Klin. Med., 40, 521. 22. Umeki S, Konishi Y, Yasuda T et al (1985) DPeniciltamine and neutrophilic agranulocytosis. Arch. Intern. Med., 145, 2271. 23. Sheldon P, Wood JK (1985) Remission of arthritis and radiological improvement after combination therapy for non-Hodg~in's lymphoma in a patient with rheumatoid arthritis undergoing treatment with d-penicillamine. ~nn. Rheum. Dis., 44, 556. 24. Gefel D, Harats N, Lijovetsky G, Eliakim M (1985) Cholestatic jaundice associated with dpenicillamine therapy. Scand. J. Rheumatol., 14, 303. 25. Stein HB, Schroeder ML, Dillon AM (1986) Peniclllamine-induced proteinuria: risk factors. Semin. Arthritis Rheum., 15, 282. 26. Rehan A, Johnson K (1986) IgM nephropathy associated with penicillamine. Am. J. Nephrol., 6, 71. 27. Sadjadi SA, Seelig MS, Berger AR, Milstoc M (1985) Rapidly progressive glomerulonephritis in a patient with rheumatoid arthriti~ during treatment with high-dosage d-penicillamine. Am. J. Nephrol., 5, 212. 28. WiUians AJ, Fordham JN, Barnes CG, Goodwin FJ (1986) Progressive proliferative glomerulonephritis in a patient with rheumatoid arthritis treated with d-penicillamine. Ann. Rheum. Dis., 45, 82. 29. Bahmer FA, Bambauer R, Stenger D (1985) Penicillamine-induced pemphigus foliaceus-like dermatosis. Arch. Dermatol., 121, 665. 30. Gibson LE, Dicken CH (1985) Pemphigus erythematosus, primary biliary cirrhosis, and dpenicillamine: report of a case. J. Am. Acad. Dermatol., 12, 883. 31. Ho VC, Stein HB, Ongley RC, Mcleod WA (1985) Penicillamine induced pemphigus. J. Rheumatol., 12, 583. 32. Piette-Brion B, De Bast C, Chamoun E et al (1985) Pemphigus superficiel apparu lors du traitement d'une polyarthrite rhumatoide par d-p6nicillamine et piroxicam. Dermatologica, 170, 297. 33. Gall Y, Guillet G, Leroy JP et al (1986) Bulles et 16sions urticariformes de vascularit6 allergique avec immunomarquage de type pemphigoide bulteuse lors d'un traitement par d-p6nicillamine. Ann. Dermatol. V~n~r~ol., 113, 55, 34. Velthuis PJ, Hendrikse JC, Nefkens JJ (1985) Combined features of pemphigus and pemphigoid induced by penicillamine. Br. J. Dermatol., 112, 615.
217 35. Stiegleder GK (1985) Penicillamin und Blasenbildung. Z. Hautkr., 21, 1653. 36. Shuttleworth D, Graham-Brown RA, Hutchinson PE, Jolliffe DS (1985) Cicatricial pemphigoid in d-penicillamine treated patients with rheumatoid arthritis: a report of three cases. Clin. Exp. Dermatol., 10, 392. 37. Kohn SR (1986) Fatal penicillamine-induced pemphigus foliaceus-like dermatosis. Arch. DermatoL, 122, 17. 38. Peyri J, Servitje O, Ribera M e t al (1986) Cicatricial pemphigoid in a patient with rheumatoid arthritis treated with d-penicillamine. J. Am. Acad. DermatoL, 14, 681. 39. Meyrick Thomas RH, Kirby JDT (1985) Elastosis perforans serpiginosa and pseudoxanthoma elasticum-like skin change due to d-penicillamine. Clin. Exp. Dermatol., 10, 386. 40. Floreani A, Chiaramonte M, Pagnes P et al (1984) Lichen planus da penicillamina in paziente con cirrose biliare primitiva. Eur. Rev. Med. PharmacoL Sci., 6, 481. 41. Weismann K, Wantzin GL, Christensen E (1986) Lichen planus red peniciUaminbchandlet primaer biliaer cirrose. Ugeskr. Laeg., 148, 456. 42. Kahl LE, Medsger TA, Klein I (1985) Massive breast enlargement in a patient receiving dpenicillamine for systemic sclerosis. J. RheumatoL, 12, 990. 43. Benson EA, Healy LA, Barron EI (1985) Insulin antibodies in patients receiving penicillamine. Am. J. Meal., 78, 857. 44. Becker RC, Martin R (1986) Penicillamineinduced insulin antibodies. Ann. Intern. Med., 104, 128. 45. Elling P, Elling H (1985) Penicillamine, captopill and hypoglycemia. Ann. Intern. Med., 103, 644. 46. D'Anglejan J, Morel E, Feuillet-Fieux MN et al (1985) Myasthtnie induite par la d-penicillamine. Presse Mbd., 14, 2336. 47. Devogelaer JP, Isaac G, Notl H e t al (1985) Neuromuscular disorders associated with d-penicillamine treatment for rheumatoid arthritis. Int. J. Clin. Pharmacol. Res., 5, 143. 48. Leden I, Libelius R (1985) Penicillamineinduced polymyositis. Scand. J. Rheumatol., 14, 90. 49. Rosa CM, Queiroz MV (1985) Um caso de polimiosite induzida pela d-penicilamina. Acta Reumatol. Port., 10, 141. 50. Crouzet J, Beraneck L (1986) Pyrithioxine et polyarthrite rhumatoide. Rev. Rhum., 53, 45. 51. Amor B, Mery C, De Gery A, Zizi M (1986) Tiopronine r polyarthrite rhumatoide. Rev. Rhum., 53, 39. 52. Ishikawa K, Sakaguchi M (1986) SA 96 (N-(2Mercapto-2-methylpropanoyl)-L-cysteine) in rheumatoid arthritis. Scand. J. Rheumatol., 15, 85. 53. Olivieri NF, Buncic JR, Chew E (1986) Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N. Engl. J. Med., 314, 869. 54. Walker JA, Sherman RA, Eisinger RP (1985)
218 Thrombocytopenia associated with intravenous desferrioxamine. Am. J. Kidney Dis., 6, 254. 55. Boyce N, Wood C, Holdsworth S e t al (1985) Life-threatening sepsis complicating heavy metal chelation therapy with desferrioxamine. Aust. N Z J. Med., 15, 654. 56. Melby K, Slordahl S, Gutteberg T J, Nordbo SA (1982) Septicaemia due to Yersinia enterocolitica after oral overdoses of iron. Br. Med. J., 285, 467. 57. Waterlot Y, Caninieaux B, Hariga-Muller C (1985) Impaired phagocytic activity 'of neutrophil in patients receiving haemodialysis: the critical role of iron overload. Br. Med. J., 291, 501. 58. Robins-Browne RM, Prpic JK (1983) Desferrioxamine and systemic yersiniosis. Lancet, 2, 1372. 59. Scharnetzky M, K6nig R, Lakomek M e t al 0984) Prophylaxis of systemic yersiniosis in thalassaemia major. Lancet, 1, 791. 60. Waterlot Y, Vanherweghem J-L (1985) Desferrioxamine en h6modialyse fi l'origine d'une septic6mie ~ Yersinia enterocolitica. Presse M$d., 14, 699. 61. Chiu HY, Flynn DM, Hoffbrand AV, Politis D
Chapter 24
R.H.B. Meyboom and LA. Jaffe
(1986) Infections with Yersinia enterocolitica in patients with iron overload. Br. Med. J., 292, 97. 62. Kelly D, Price E, Wright Vet al (1986) Yersinia and iron overload. Br. Med. J., 292, 413. 63. Proksch E, K61mel K (1985) Zinkmangelsyndrom als Nebenwirkung von Chelatbildern. Dtsch. Med. Wocher~chr., 110, 1001. 64. Magee R (1985) Chelation treatment of atherosclerosis. Med. J. ,,lust., 142, 514. 65. Casals FJ, Alfonso L, Alonso A e t al (1985) Seudotrombocitopenia como causa de diagnostico erroneo de la enfermedad de Werlhof. Med. Clin. Barcelona, 84, 721. 66. Feliu E, Gardella S (1985) Seudotrombocitopenia por extraction de sangre con acido etilendiamino-tetraacctico (EDTA): un causa de error diagnostico. Med. Clin. Barcelona, 84, 738. 67. Grau Segura E, Fontcuberta Boj J, Felez Brugues J (1985) Seudotrombocitopenia y seudoleucocitosis. Med. Clin. Barcelona, 84, 754. 68. GardeUa S, Feliu E, Labal F et al (1985) Seudotrombocitopenia pot EDTA" posible causa de un diagnostico erroneo de enfermedad de Werlhof. Med. Clin. Barcelona, 84, 755.