Rheumatic syndromes caused by antirheumatic drugs

9 Rheumatic syndromes caused by antirheumatic drugs P. J. ROON,EY G I)ZA P. BALINT BELA SZEBENYI PETROS PETROU

There is an old adage for physicians dealing with chronic diseases: 'Always be sure to offer your patients some form of treatment--if they get better you can take the credit--if they get worse the disease is progressing'. Unfortunately the advent of highly potent medications has rendered such advice dangerous. Side-effects of medication are a major cause of morbidity and even mortality in modern medicine. Antirheumatic drugs suffer from this problem at least as commonly as any other class of therapeutic agents. Indeed, 7% of admissions to a rheumatic disease unit in the seventies consisted of patients admitted because of drug side-effects (Lee et al, 1973). The detection of the side-effects of antirheumatic drugs is generally easy when such side-effects predominantly affect organ systems outside the musculoskeletal system. For example, dyspepsia following the start of treatment of inflammatory joint disease is readily attributable to prescribed non-steroidal anti-inflammatory drugs (NSAIDs). It can be a little more difficult when the symptoms and/or pathology involve systems which are commonly affected by the disease being treated. For example, shortness of breath in systemic lupus erythematosus (SLE) may be a feature of pulmonary involvement by the disease, or may be due to bronchospasm or cardiac failure induced by NSAIDs. The most difficult diagnostic problem of all exists when the drug used to treat the rheumatic disease induces side-effects in the musculoskeletal system itself. It is this last group of problems which form the focus of this chapter. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs are among the most commonly prescribed drugs at the present time and the overwhelming indication for their use is the alleviation of musculoskeletal pain. Thus, they are used in almost all types of musculoskeletal disease (Paulus and Furst, 1985) and it is easy to understand why it might prove difficult to attribute musculoskeletal disorders to these drugs. Bailli~re's Ctinical Rheumatology-Vol. 5, No. 1, April 1991 ISBN 0-7020-1535-0

139 Copyright 9 1991, by BaiUihre TindaU All rights of reproduction in any form reserved

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Osteoarthritis

Mechanical wear on joints and joint cartilage is a major component of the aetiology of osteoarthritis. There is a constant interaction between movement, the forces through the joint, and the strength and integrity of the structural components. Osteoarthritis will not occur if a joint is immobile or paralysed (Glyn et al, 1966; Thirupathi et al, 1984). The reduction of pain by means of simple analgesics or NSAIDs (Huskisson et al, 1985) may permit increased mobility or increased mechanical forces through the joint and so accelerate joint damage. It has been suggested since the early 1960s that NSAIDs may be toxic to cartilage (Dixon and Wanka, 1964; Arora, 1968; Milner, 1973). Ronningeu and Langeland in 1979, and Newman and Ling in 1985, offered evidence of such toxicity from indomethacin use, and these articles are widely quoted, although they do not stand up well to critical review (Lequesne and Lamotte, 1990). The 1989 paper of Rashad et al offers what on first glance appears to be good evidence of this effect, but again Lequesne and Lamotte (1990) have shown that this paper does not stand up to critical review and conclude that the case for damage to cartilage caused by NSAIDs is at best not proven. Equally, a number of papers have failed to demonstrate this effect (Watson, 1976; Lequesne and Ray, 1989). More recently the evidence favours the opposite concept--a protective effect of NSAIDs. In experimental models of osteoarthritis in animals a number of NSAIDs have been shown to reduce cartilage damage (Butler et al, 1983; Colombo et al, 1983; Maier and Wilhelmi, 1984; Williams and Brandt, 1985). This controversy has led to a significant increase in the investigation of cartilage biochemistry and metabolism (Hess and Herman, 1986; Pelletier and Martel-Pelletier, 1989; Nietfeld et al, 1990) and of the effects of NSAIDs on such processes (McKenzie et al, 1976; Herman et al, 1986; Hess and Herman, 1986; Verbruggen et al, 1989; Vignon et al, 1990). At the moment there are no clinical conclusions to be reached from these studies, but they may well prove to be important in the future in the long-term management of osteoarthritis. Gout

NSAIDs represent the primary treatment for acute gout (Wilkens et al, 1975; McCarty, 1985), with indomethacin being widely considered the agent of first choice. The efficacy of these agents is directly related to their anti-inflammatory effect. Virtually all NSAIDs are in addition potent uricosuric agents. However, acetylsalicylic acid (aspirin BP, USP) is considered to be contraindicated in gout and has been implicated in triggering attacks of acute gout (Yti and Gutman, 1959), although how significant this is in clinical practice is a little doubtful. DISEASE MODIFYING AND REMITTING DRUGS

The so-called disease modifying and remitting drugs (DMARDs) are agents that are widely used for treating progressive rheumatoid arthritis (RA) not

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satisfactorily controlled by NSAIDs. They include gold, antimalarials, D-penicillamine, sulphasalazine and levamisole. It should be noted that the clinical use of these drugs is not limited exclusively to RA. Gold is also used successfully in certain cases of psoriatic arthritis, antimalarials for SLE and discoid lupus, D-penicillamine for Wilson's disease, and scleroderma and sulphasalazine not only for ulcerative colitis, but also for rheumatoid arthritis and some forms of seronegative spondyloarthropathy. Although the mode of action of these drugs is not well understood, most of them probably influence the function of the immune system. This might explain the intriguing fact that some of them--especially D-penicillamine--not only cause rheumatic symptoms and signs, but also induce autoimmune diseases. This has important theoretical and practical implications. Studying the drug-induced autoimmune diseases may yield clues for better understanding of the naturally occurring ones. Equally important in practice, the rheumatic symptoms and signs caused by antirheumatic drugs may be easily overlooked, being regarded merely as symptoms and signs of the underlying rheumatic disease. D-Penicillamine

D-Penicillamine is certainly the most interesting of the DMARDs causing rheumatic symptoms and signs. It certainly has the potential for inducing autoimmune diseases. It has been reported to cause a number of syndromes including Goodpasture's syndrome (Sternlieb et al, 1975; Gibson et al, 1976), myasthenia gravis (Ott and Schmidt, 1974; Bfilint et al, 1975; Bucknall et al, 1975), polymyositis (Schraeder et al, 1972; Nishikai et al, 1974), Moschcowitz syndrome (Bettendorf and P6tters, 1975), pemphigus (Benveniste et al, 1975), SLE (Harpey et al, 1971; Crouzet et al, 1974), Sj6gren's syndrome (Bucknall et al, 1975; May et al, 1977) and autoimmune thyroiditis (Delrieu et al, 1976). These syndromes may develop not only in patients with RA but in patients with Wilson's disease (Harpey et al, 1971; Schraeder et al, 1972; Czlonkowska, 1975), cystinuria (D'Anglejan et al, 1985), scleroderma (Niotshikai et al, 1974; Torres et al, 1980), primary biliary cirrhosis (Marcus et al, 1984) and psoriatic arthritis (Ferbert, 1989), excluding the possibility that the altered immune status existing in RA is alone responsible for the development of D-penicillamine-induced autoimmune syndromes.

o-Penicillamine-induced myasthenia gravis Myasthenia gravis is the autoimmune disease reported most frequently during the course of D-penicillamine treatment. Although it has been reported due to o-penicillamine treatment of Wilson's disease (Czlonkowska, 1975; Masters et al, 1977; Garlepp et al, 1982), scleroderma (Torres et al, 1980; Steen et al, 1986), biliary cirrhosis (Marcus et al, 1984), psoriatic arthritis (Ferbert, 1989) and cystinuria (D'Anglejan et al, 1985), most cases of myasthenia gravis have occurred in RA (Dawkins et al, 1981b; Ferbert, 1989). A significant factor in this preponderance may be the

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immunological abnormalities that occur due to RA alone (Bucknall et al, 1979; Szobor et al, 1979).

Epidemiology. The prevalence of RA in spontaneously occurring myasthenia gravis ranges from 0.8 to 8.3 % (Downes et al, 1966; Simpson, 1966; Wolf et al, 1966; Oosterhuis and de Haas, 1968; Szobor et al, 1979). On the other hand, the prevalence of myasthenia gravis in RA seems to be much lower. Sundstrom and Schuna (1979) had only one patient with concomitant myasthenia out of their 400 RA patients (0.25%), although this is certainly higher than the prevalence of myasthenia gravis in the normal population, which is about 30-60 per million (Kurlana and Alter, 1961). While Dawkins et al (1981a) concluded that coexistence of myasthenia gravis and RA in the absence of penicillamine may be explicable in terms of chance alone, in RA patients treated with D-penicillamine, myasthenia gravis probably coexists in as many as approximately 1-6% of cases (Dawkins et al, 1981b). Wisocka et al (1981) provided very similar incidence figures.

Aetiology, geneticsand immunology. In the early reports of D-penicillamineinduced myasthenia gravis differences in the clinical course of the disease were clearly delineated. In all four patients of Bucknall et al (1975) the myasthenia remitted completely after discontinuation of o-penicillamine treatment. This contrasted sharply with the experience of Bfilint et al (1975), where discontinuation of treatment did not resolve the problem. Thymic hyperplasia was detected in a number of cases, and one patient required thymectomy and another thymus irradiation (Bfilint et al, 1975; Bucknall et al, 1975; Szobor et al, 1979). In subsequent reports, the former course of o-penicillamine-induced myasthenia gravis proved to be more prevalent, although the number of cases associated with thymus hyperplasia also increased significantly (Vincent et al, 1978; Wysocka et al, 1981). This observation raised the possibility that, at least in some cases, o-penicillamine had unmasked latent myasthenia (Szobor et al, 1979; Argov et al, 1980). However, the demonstration that the genetic predisposition to o-penicillamine-induced myasthenia gravis is quite different from that to spontaneous myasthenia gravis has seriously weakened this concept. While spontaneous myasthenia gravis occurs mainly in subjects with human leukocyte antigen (HLA) B8 and DR3 (Behan et al, 1973; Feltkamp et al, 1974; Delamere et al, 1983), o-penicillamine-induced myasthenia gravis occurs mainly in subjects with HLA Bw35 and DR1 (Garlepp et al, 1982; Delamere et al, 1983; Dawkins et al, 1987). Delamere et al (1983) state that the presence of HLA B8 and DR3 may even protect against D-penicillamineinduced myasthenia gravis. Interestingly, when o-penicillamine causes proteinuria, which is mostly due to immune complex nephritis, this is also associated with HLA B8 and DR3 (O'Keefe et al, 1985; Stockman et al, 1986). Out of our own series of ten patients with •-penicillamine-induced myasthenia gravis, seven patients have been tissue typed. HLA DR1 was found in three, HLA DR5 also in three, and HLA Bw35 in one case. No

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specific genetic association with thymic hyperplasia was evident. In one patient who required thymectomy the HLA pattern was more characteristic of spontaneously occurring myasthenia gravis (HLA A1, HLA B8, HLA DR3), but the course of his disease was not different from that of the other D-penicillamine-induced myasthenia gravis patients (B~lint et al, 1984). It is of interest to note that of the four systemic sclerosis patients of Steen et al (1986), all also had HLA DR5. This antigen is relatively common in restricted ocular myasthenia gravis, which occurs especially in Chinese patients (Dawkins et al, 1987). Antibodies against the acetylcholine receptor (AChR) are characteristic for both forms of myasthenia gravis (Masters et al, 1977; Russel and Lindstr6m, 1978; Vincent et al, 1978; Carter et al, 1984; D'Anglejan et al, 1985). Although some authors have found some differences in the antiAChR antibodies formed in D-penicillamine-induced myasthenia gravis and spontaneous myasthenia gravis (Dawkins et al, 1981b; Vincent and Newsom-Davis, 1982; D'Anglejan et al, 1985), Tzartos et al (1988), studying the five antigenic specificities of the anti-AChR antibodies in both D-penicillamine-induced and spontaneous myasthenia gravis, have found that the antibody repertoire in the sera is very similar (Tzartos et al, 1988). The other immunological finding in D-penicillamine-induced myasthenia gravis is the presence of antistriational antibodies in about 20-53% of the cases. These antibodies are not usually found in spontaneous myasthenia gravis, except when it is associated with thymoma (Dawkins et al, 1981c). These antibodies can be found with similar frequency in D-penicillaminetreated RA patients (Masters et al, 1977; Dawkins et al, 1981c). Pathomechanism. The pathomechanism of D-penicillamine-induced myasthenia gravis is still unclear. A direct effect is unlikely, since there is no temporal relationship between the D-penicillamine treatment and the myasthenia gravis (Masters et al, 1977; Bucknall et al, 1979; Delamere et al, 1983; Ferbert, 1989). The fact that D-penicillamine-induced myasthenia can be transferred from mother to neonate (Masters et al, 1977) and the strong correlation between anti-AChR antibodies and the clinical disease argue for a mechanism similar to spontaneous myasthenia gravis (Dawkins et al, 1981c). It has been suggested that D-penicillamine may enhance the production of low-titre AChR antibodies (Fawcett et al, 1982). Scadding and Newsom-Davis (1983), however, found no in vitro effect of D-penicillamine upon the AChR antibody production by thymic and peripheral blood lymphocytes from patients with myasthenia gravis. D-Penicillamine may lead to an alteration in relevant autoantigens or it may have some influence on immune regulation (Dawkins et al, 1981b). Hapten formation between penicillamine and AChR might be expected to elicit production of antibody to the receptor, leading to the development of myasthenia (Bever et al, 1982). Human peripheral blood lymphocytes, both from healthy individuals and patients with D-penicillamine-induced myasthenia gravis, gave a weak proliferation response after in vitro D-penicillamine exposure. Smith et al (1982), Fawcett et al (1982) and McLachlan and Fawcett (1983) demonstrated stimulation of polyclonal immunoglobulin (Ig) G synthesis and

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increased AChR antibody synthesis by human lymphocytes. However, this activating effect of D-penicillamine was not observed in all cultures of normal donors, raising the possibility that this stimulatory effect is restricted to particular individuals who might be at risk if exposed to the drug (McLachlan and Fawcett, 1983). Thus it is possible that the drug, by binding to certain self-molecules, could serve as an activating ligand for cells binding to these molecules (Smith et al, 1982). If the drug were to bind to AChR in muscles or in the thymus, it is possible that B cells with immunoglobulin surface receptors corresponding to the same site could be activated by penicillamine (Smith et al, 1982). Tzartos et al (1988) suggest that, if D-penicillamine exerts its effect by modifying the AChR, this modification is probably very similar to the putative modification of the AChR in spontaneous myasthenia gravis. Their investigations strongly suggest that the immunogen in both diseases is the AChR itself, rather than other crossreactive antigens (Tzartos et al, 1988). AChR antibodies may be present months before the symptoms of D-penicillamine-induced myasthenia gravis develop (Kolarz and Maida, 1986) or even in RA patients on D-penicillamine treatment without symptoms and signs of myasthenia (Martin et al, 1980; Vincent and Newsom-Davis, 1982; Kolarz and Maida, 1986). In rats, D-penicillamine causes a mild presynaptic effect on neuromuscular transmission (Aldrich et al, 1979). In one of our patients structural abnormalities developed in the neuromuscular junction, with disorganization and even destruction of the postsynaptic apparatus (Bucknall et al, 1979). It is of interest that thymic hyperplasia was consistently found in rhesus monkeys after prolonged administration of penicillamine (Jakobus et al, 1976). Clinical features and course. The clinical patterns of spontaneously occurring and D-penicillamine-induced myasthenia gravis are indistinguishable. Both may start as ocular myasthenia, later becoming generalized, or may present as generalized myasthenia from the beginning (Balint et al, 1975; Bucknall et al, 1975; George and Spokes, 1984; O'Keefe et al, 1985). Both respond promptly to intravenous edrophonium. The doses and duration of D-penicillamine treatment inducing myasthenia gravis vary very widely (Bucknall et al, 1979; Delamere et al, 1983; Carter et al, 1984; Ferbert, 1989). The patient of Atcheson and Ward (1978) received only 250 mg/day and noticed weakness within 48 hours. AChR antibodies are detectable in about 75-100% of patients (Dawkins et al, 1981c; Vincent and Newsom-Davis, 1982; Carter et al, 1984; D'Anglejan et al, 1985). These titres fall quickly after discontinuation of o-penicillamine therapy (Vincent et al, 1978). Antistriational antibodies--the presence of which is unusual in spontaneous myasthenia gravis--can be detected in 20% of D-penicillamineinduced myasthenia gravis patients (Masters et al, 1977). Discontinuation of D-penicillamine treatment usually, but not always, results in improvement of the myasthenia gravis (Argov et al, 1980; Delamere et al, 1983). Full recovery, however, takes a few weeks or months, and usually requires pyridostigmine therapy (B~lint et al, 1975; Bucknall et al, 1975; Gordon and Burnside, 1977). In patients with thymic hyperplasia, thymectomy or thymic irradiation, plasmapheresis or plasma exchange may be required to control

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the disorder (Bfilint et al, 1975; Vincent et al, 1978; Lang et al, 1981; Wysocka et al, 1981; D'Anglejan et al, 1985). Subsequent repeat challenge to patients with o-penicillamine did not result in a recurrence of the myasthenia gravis in the one thymectomized patient of Czlonkowska (1975), but did so in the patients of Seitz et al (1976). One of the patients reported in the literature died due to respiratory failure (Bucknall et al, 1979) and a few have had only incomplete remissions (Delamere et al, 1983). The first patient of Bftlint et al (1975) still requires occasional pyridostigmine treatment, although she subsequently gave birth to two healthy children (G. Bgdint and A. Szobor, unpublished data).

Diagnosis. The diagnosis of D-penicillamine-induced myasthenia gravis is not easy, especially in RA, because the complaints of weakness and fatigue might be regarded as symptoms of RA. The ocular and bulbar symptoms and signs, or the developing generalized weakness should, of course, raise suspicion. In a number of cases probably only mild myasthenic signs develop without overt myasthenia gravis (Masters et al, 1977). Intravenous edrophonium causes an immediate improvement in muscle strength. The electromyogram (EMG) findings are not always characteristic of myasthenia gravis, but there should be no signs of myopathy. D-Penicillamine-induced myasthenia gravis must be distinguished from D-penicillamine-induced polymyositis (Atcheson and Ward, 1978). It is not associated with elevated levels of muscle enzymes, and muscle biopsies are usually normal or show type 2 fibre atrophy (Seitz et al, 1976). Chronic inflammatory changes are inconspicuous or absent.

Polymyositis and dermatomyositis D-Penicillamine-induced polymyositis (PM) was described earlier than the drug-induced myasthenia (Schraeder et al, 1972; Bettendorf and Neuhaus, 1974; Nishikai et al, 1974). Schraeder et al (1972) reported the first case of D-penicillamine-induced polymyositis in a patient with Wilson's disease (Schraeder et al, 1972). This was followed by the report of Nishikai et al (1974) concerning a progressive systemic sclerosis (PSS) patient treated with the drug. The first patient to develop PM during D-penicillamine treatment for R A was reported by Bettendorf and Neuhaus (1974). This report was soon followed by several others (Cucher and Goldman, 1976; Petersen et al, 1978; Ostensen et al, 1980; Brousson et al, 1981). Dermatomyositis (DM) occurring in RA due to D-penicillamine was reported by Fernandes et al (1977) and Wojnarowska (1980). The first case to occur in a patient with juvenile chronic arthritis patient was reported by Swartz and Silver (1984). D-Penicillamine may induce multiple autoimmune pathological events. The concurrence of both PM and myasthenia gravis has been reported (Essigman, 1982). Carroll et al (1987), in eight patients with o-penicillamine-induced PM/DM, found anti-AChR antibodies in two, but neither had any symptoms of myasthenia. This antibody very rarely occurs in spontaneous DM or PM (Dawkins et al, 1981a) and the authors suggested that the two patients might have had latent myasthenia. Thus, the muscular pathology might represent an acute inflammatory phase of myasthenia

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analogous to that seen in experimental autoimmune myasthenia (Lennon et al, 1975).

Epidemiology and clinical features. The coincidence of RA and spontaneously occurring DM/PM is very rare (Pitkeathly and Coomes, 1966; Takahashi et al, 1986). Focal myositis without elevation of muscle enzyme levels is common in RA (Steiner et al, 1946; Horwitz, 1949), but frank polymyositis is rare. Pitkeathly and Coomes (1966) described a welldocumented case in 1966. Medsger et al (1970) estimated the coincidence of RA and PM/DM to be lower than 0.001%. m-Penicillamine-induced PM/DM occurs in RA with a frequency of between 0.4 and 1.2% (Dawkins et al, 1981a; Takahashi et al, 1986). The clinical and pathological features of D-penicillamine-induced DM/PM are indistinguishable from the spontaneously occurring disease. Fulminant fatal cases due to cardiac involvement may occur (Bettendorf and Neuhaus, 1974; Doyle et al, 1983). Acute myolysis has also been described (Ostensen et al, 1980). The only features that distinguish the drug-induced disease are that it occurs during D-penicillamine therapy, the cessation of which causes the symptoms and signs to subside (Carroll et al, 1987). In some cases this remission may take a long time and require steroid treatment (Takahashi et al, 1986; Carroll et al, 1987). In spite of the fact that fatalities do occur, the course of D-penicillamine-induced PM/DM seems to be more benign (Carroll et al, 1987). D-Penicillamine-induced DM/PM may occur on doses as low as 100rag/day (Takahashi et al, 1986), although it is more likely at higher doses. Resumption of treatment may once more induce the symptoms and signs of DM/PM (Takahashi et al, 1986; Carroll et al, 1987), although in a few cases repeat challenge with a lower dose of I>penicillamine and concomitant steroids avoided such a recurrence (Halla et al, 1984). Interestingly, Ostensen et al (1980) have reported recurrence of polymyositis in some patients subsequently exposed to ampicillin. The molecular structures of D-penicillamine and ampicillin share significant similarities.

Pathogenesis. The pathogenesis of 9-penicillamine-induced PM/DM is unclear. It is well recognized that D-penicillamine can induce autoantibodies (Crouzet et al, 1974; Carrano et al, 1983). These authors showed that among a group of 150 RA patients, 12 months' treatment with D-penicillamine induced the development of antinuclear antibodies (ANA) in significant titre in up to 67 %. All of the patients reported by Carroll et al (1987) were ANA-positive at the time of developing polymyositis. Unlike idiopathic PM, none of the cases of Nishikai and Reichlin (1980) were positive for antibodies to extractable nuclear antigen (ENA). Antistriational antibodies frequently develop in RA patients treated by D-peniciUamine (Carrano et al, 1983), and this is not an unusual finding in o-penicillamine-induced PM/DM (Carroll et al, 1987). The same authors described C2 deficiency in three out of six o-penicillamineinduced PM/DM patients. It is of note that idiopathic PM has also been described secondary to C2 deficiency (Leddy et al, 1975). Anti-DNA antibodies were detected in RA patients developing D-penicillamine-induced PM/DM without any other evidence of SLE (Takahashi et al, 1986).

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The immunogenetic characteristics of D-penicillamine-induced PM/DM, like that of D-penicillamine-induced myasthenia gravis, have been fairly thoroughly investigated because it was hoped that studying the Dpenicillamine-induced forms might yield some clues to the aetiology of the idiopathic disease. Surprisingly, in the series of patients studied by Carroll et al (1987), they found an association with H L A B18, B35 and DR4 in D-penicillamine-induced PM/DM, while in idiopathic PM/DM the occurrence of B8 and DR3 haplotypes are increased (Garlepp et al, 1982; Carroll et al, 1987). These results would suggest that D-penicillamine-induced PM/DM is immunogenetically different from the idiopathic form. The possibility arises that a particular subset of patients with R A may be susceptible to PM/DM when exposed to D-penicillamine (Carroll et al, 1987).

Diagnosis. The diagnosis of D-penicillamine-induced PM is not difficult, even if it occurs in RA patients. The pronounced muscular weakness-which is not characteristic of R A - - t h e rise in muscle enzymes and the EMG and muscle biopsy patterns are diagnostic for PM. However, differentiating this disorder from D-penicillamine-induced myasthenia gravis is sometimes very difficult (Carroll et al, 1987), especially when AChR antibodies are present. This is an unusual feature of spontaneously occurring PM and more characteristic of spontaneous or drug-induced myasthenia gravis (Dawkins et al, 1981a). The two drug-induced diseases have also been reported in the same patient (Essigman, 1982). Treatment. When treating D-penicillamine-induced DM/PM the essential first step is to discontinue the drug. In milder cases this may be all that is necessary as the symptoms and signs of polymyositis may subside within a few weeks or months (Carroll et al, 1987). In more severe cases, medium- or high-dose steroid treatment may be needed (Takahashi et al, 1986; Carroll et al, 1987). Although some patients have been rechallenged following resolution without any relapse of PM/DM (Schraeder et al, 1972), this has sometimes been possible only when steroid treatment has been continued (Halla et al, 1984). We consider rechallenging to be very hazardous and do not advise it, unless the use of D-peniciUamine is critical for the management of the patient, as in Wilson's disease. Other autoimmune diseases induced by D-penicillamine We have already listed and referenced many of the autoimmune syndromes which have been reported as complications of D-penicillamine treatment. In a number of patients more than one autoimmune syndrome has developed. Out of the patients reviewed by Bucknall et al (1979), three myasthenic patients developed autoimmune thyroiditis. One of the patients of Delamere et al (1983) developed an SLE-like syndrome, but with a high anti-DNA antibody titre, which is unusual for drug-induced SLE. Three of the patients of Stockmann et al (1986) developed SLE, but none of them possessed the H L A DR3 allele commonly associated with spontaneous

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SLE. Perhaps the most interesting patient was reported by Essigman (1982). This rheumatoid patient developed proteinuria, erythema annulare, SLE, myasthenia gravis and polymyositis, all of which improved when D-penicillamine was discontinued. Although D-penicillamine has been used to treat scleroderma, it has been implicated as a cause of the disease as well (Liddle, 1989). o-Penicillamine can induce a number of different autoantibodies (Camus et al, 1976, 1981; Dawkins et al, 1981a; D'Anglejan et al, 1985; Kolarz and Maida, 1986), although the mechanism of their production is still not fully understood. It has been hypothesized that the drug may have an effect on a subpopulation of T lymphocytes which results in immune enhancement and in a selective loss of tolerance of self-antigens (Jaffe, 1989). It has been shown that o-penicillamine and copper salts have an inhibitory effect on human helper T lymphocytes (Lipsky and Ziff, 1980), and there exists a distinct subpopulation of CD4 lymphocytes which act as inducers of CD8 suppressor cells. Inhibition of this CD4 subset by Dpenicillamine may be responsible for a selective decrease in suppressor function, leading to autoimmunity (Morimoto et al, 1983, 1985). However, full clarification of the autoimmunity caused by D-penicillamine seems to be the task of further rigorous research.

Other side-effects of D-penicillamine presenting as musculoskeletal symptoms and signs Mjolnerold et al (1971) reported a baby with a congenital disorder of connective tissue which may have been due to o-penicillamine treatment during pregnancy. The clinical and post-mortem findings resembled EhlersDanlos syndrome. Reeback et al (1979) reported an RA patient treated with 750 mg/day of D-penicillamine, later reduced to 500 mg/day, who developed, clinically and electromyographically, classic myotonia. No underlying disease was found. Sturrock and Brooks (1974) reported on three patients who noted unusual creaking of their knee joints which started during D-penicillamine therapy. Neither the cause of this phenomenon nor its relationship to D-penicillamine treatment has been established. No other similar findings have been reported to date. Gold

Gold was first introduced into the therapy of rheumatic disease by Forestier in 1929. After more than half a century it remains one of the most useful compounds for the control of inflammatory RA. However, its use is limited as much by its side-effects as by a lack of efficacy. As was noted, its use is not limited to RA but its beneficial effect does appear to be greatest in peripheral inflammatory joint disease (Skosey, 1985). The overall incidence of toxicity depends on the type of gold compound used (Lawrence, 1976), the sulphoxidation status (Panayi et al, 1983) and the genetic make-up of the patient (Gran et al, 1983). Oral gold--auranofin--is believed to be four times safer than parenteral preparations (Blodgett et al,

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1984), but the efficacy of oral gold may not be as great as with parenteral injection. A double-blind trial of high versus conventional dosages of gold has proved that while the remission-inducing effect was practically the same, the incidence of side-effects was higher in the high-dose group (Furst et al, 1977). The genetic background of gold-induced toxicity has been investigated by several authors. The presence of HLA DR3 antigen is associated with a 32 times greater relative risk for proteinuria (Panayi, 1980). Wooley and co-workers (1980) have published similar results, but the genetic background of the most common side-effects such as dermatitis and stomatitis has not yet been demonstrated (Bensen et al, 1984). Side-effects of chrysotherapy which affect the locomotor system, and thus may resemble the signs and symptoms of rheumatic diseases, are rare and occur mainly in two forms (Gordon, 1989): 1. 2.

Post-injection, non-vasomotor reactions, such as myalgia, arthralgia and a flare-up of arthritis. Nervous system side-effects, including peripheral neuropathies.

There are two types of post-injection reactions: a rapid onset vasomotor type presenting with weakness, dizziness, nausea and facial flushing, and a slower onset non-vasomotor type reaction which includes transient arthralgia, joint swelling, fatigue and malaise. The first type of reaction occurs immediately after the injection, whereas the latter develops generally about 6 to 24 hours later. The prevalence of the early non-vasomotor type is about 15 % (HaUa et al, 1977). Both types of post-injection reaction occur only with sodium aurothiomalate (gold sodium thiomalate USP) and generally do not constitute a reason for stopping treatment (Gordon, 1989). Neurological side-effects of gold are generally rare; their prevalence is between 0.2 and 0.5%. Until now about 100 cases have been reported (Doyle and Cannon, 1950; Schlumpf et al, 1983; Fam et al, 1984). It is most commonly caused by aurothiomalate, but neuropathies caused by aurothioglucose, aurothiopropanol sulphonate and auranofin have also been reported (Bontoux et al, 1974; Dougados and Amor, 1982; Gambari et al, 1984). The toxic side-effects of gold therapy affecting the central, peripheral and autonomic nervous systems can be divided into two main groups: encephalopathy and neuropathy (Fam et al, 1984). The first of these is difficult to diagnose and rarely raises any suspicion of gold toxicity. This is especially true in elderly patients who may present with focal signs, such as hemiplegia, paraplegia or aphasia, or with psychiatric syndromes, such as depression, insomnia, memory disturbance or hallucinations. Many of these symptoms and signs of depression may be mistaken for reactive depression due to the diminishing quality of life, and others, especially in the elderly, may be mistaken for arteriosclerotic cerebrovascular disease. The most common presentation of gold neuropathy is an acute, predominantly distal, symmetrical, mixed sensory and motor polyneuropathy and polyneuritis (Doyle and Cannon, 1950; Fam et al, 1984). Clinically, the type of neuropathy might be sensory, motor or sensorimotor. The nerve conduction tests and EMG examination show decreased sensory and motor

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conduction velocities, signs of denervation and sometimes spontaneous repetitive discharges of motor unit potentials, especially when myositis is present. Sural nerve biopsies show axonal degeneration and fragmental demyelinization (Schlumpf et al, 1983). The other, less common form of gold-induced polyneuropathy is an acute, severe polyneuropathy of the Guillain-Barr6 type, characterized by symmetrical, ascending motor weakness, areflexia, distal sensory impairment and characteristic patterns of dissociation of the cerebrospinal fluid (Dick and Raman, 1982). Rarely Miller-Fischer syndrome (Guillain-Barr6 syndrome with ophthalmoplegia) also occurs during gold therapy (Roquer et al, 1985); equally rare is a syndrome resembling amyotrophic lateral sclerosis. The first of these usually occurs during conventional therapy, whereas the latter has been more associated with unusually high doses (150 mg per week or more) of aurothiomalate treatment (Furst et al, 1977). The different types of polyneuropathies, especially the distal, mixed sensorimotor neuropathy and acute polyneuropathy of the Guillain-Barr6 type, may all occur in the same patient. Vernay et al (1986) reported a case history where at first only peripheral neuropathy was observed, associated with a severe form of myokymia--generalized, slow, rippling, undulating movements of the muscles involved ('chor6e fibrillaire de Morvan') (Calderon et al, 1987). Withdrawal of gold caused complete remission, but when gold therapy was resumed with a low dose of aurothiopropanol, a typical Guillain-Barr6 syndrome developed, which involved even the respiratory muscles and required assisted ventilation and plasmapheresis (Vernay et aI, 1986). The mechanism of the neurological complications due to gold treatment is unknown. The lack of any association with dose in most instances suggests a hypersensitivity reaction, although, like other heavy metals, gold certainly has a direct toxic effect on nervous tissue. The prognosis of these toxic side-effects of gold therapy is generally favourable. After withdrawal of the gold treatment, most of the severe neurological symptoms and signs, including any focal lesions, recover within some weeks (Schlumpf et al, 1983; Faro et al, 1984). Although it has been recognized that there may be cross-toxicity between gold and D-penicillamine (Webley and Coomes, 1978; Dodd et al, 1980; Smith et al, 1982), the report of Moore et al (1984) is still unique. They published an interesting case history in a RA patient where penicillamineinduced myasthenia was reactivated 1 year later following five injections of 10 mg of sodium aurothiomalate.

Antimalarial drugs The musculoskeletal side-effects of the antimalarial drugs used in rheumatology are relatively rare compared with the other well-known toxic reactions (skin rash, gastrointestinal and eye toxicity). However, myopathy, neuromyopathy and myasthenia (Rynes, 1989) have been associated with these drugs.

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The overall toxicity of antimalarials has been overemphasized in the earlier open studies, where toxicity was reported in up to 60-70% of the patients treated (Rynes, ]989). A more recent comparative trial concluded that patients treated with antimalarials have the lowest risk (30%) of developing complications compared with levamisole (67 %), gold (44%) and penicillamine (50%) (Husain and Runge, 1980). The difference between the overall toxic effects of chloroquine and hydroxychloroquine has not been extensively studied, but one report suggests that retinal toxicity may occur more frequently when chloroquine is used (Finbloom et al, 1985). The first report of chloroquine neuropathy was published in the early sixties. The authors described seven patients who developed weakness in the proximal muscles of the limbs, and sometimes also in the trunk, neck and facial muscles. Tendon reflexes were usually absent or reduced without any sensory loss. Electromyography showed signs both of myopathy and neuropathy, with some muscles having an increased proportion of low amplitude polyphasic motor unit action potentials, while others had predominantly a reduced number of normal or polyphasic potentials. Histology showed scattered degenerating muscle fibres, although one case also showed severe vacuolar changes in the muscle. The dose of chloroquine given varied between 250 and 500 mg/day, and the duration of treatment ranged from a few weeks to more than 1 year (Whisnant et al, 1963). Additional cases of chloroquine myopathy or neuromyopathy were published by Begg and Simpson (1964) and by Ebringer and ColviUe (1967). These latter authors described severe chloroquine-induced myopathy, associated with keratopathy and neuropathy. They also noted that the histologically observed vacuolar changes in the muscle reported by Whisnant et al (1963) had been previously described in chloroquine-treated SLE patients (Rynes, 1989). Comprehensive studies on chloroquine myopathy were published by Hughes et al (1971). They observed a positive histochemical reaction to myofibrillar succinic dehydrogenase, but the reaction to adenosine diphosphatase and phosphomyolase was negative, proving that mainly granular (type 1) muscle fibres are affected in chloroquine-induced myopathy. Electron microscopy showed extensive degeneration of the muscle fibres with mitochondrial changes. All these ultrastructural changes were similar to those in experimental chloroquine-induced myopathy in animals. Although Hughes et al (1971) felt that toxic myopathy was dose related, Ebringer and Colville (1967) published a case where the severity of the toxic reaction was felt to be associated not with the dose (250mg/day), but rather with the duration of the treatment (18 months) (Ebringer and Colville, 1967). A recent study summarizes all the clinical, electrophysiological and histological features of chloroquine neurotoxicity. They include the earlier observed vacuolar changes, which may also be present in SLE patients never treated with chloroquine. They also describe some specific histological features--'curvilinear bodies' and 'myelin accumulation' derived from lysosomes (Estes et al, 1987). Chloroquine has also been implicated in the development of myasthenia gravis. In 1981 Schumm et al reported a RA patient who developed

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myasthenia gravis after two months of 250 mg/day chloroquine treatment. They found increased titres of AChR antibodies, but it was not clear whether this represented a drug-induced myasthenia gravis or latent myasthenia manifested by the drug treatment (Schumm et al, 1981), Recently it has been suggested that chloroquine may have a direct toxic effect on the neuromuscular junction. A possible mechanism of action (preor postsynaptic) has been postulated, and the authors speculate why chloroquine is so rarely associated with myasthenia. The exact answer remains unclear, but according to their hypothesis a 'safety factor' of the neuromuscular transmission might exist, which is absent or reduced in patients sensitive to the drug (Robberecht et al, 1989). In a recent report (Sghirlanzoni et al, 1988) the side-effects of myopathy and myasthenia both occurred in one patient. Their young SLE patient was treated with chloroquine. She first developed chloroquine myopathy, then after restarting the drug, a myasthenia-like syndrome. They found alterations in the muscle biopsy specimens which fulfilled the diagnostic criteria of chloroquine myopathy--widespread vacuolization with autophagia, myeloid and curvilinear bodies. As in the case described by Schumm et al (1981), this patient also demonstrated anti-AChR antibodies.

Levamisole

The immunomodulatory drug, levamisole, was widely used for treating rheumatic diseases, aphthous stomatitis and malignancies during the late seventies and early eighties. Out of the numerous side-effects caused by the drug, only a few related to rheumatic complaints. A flu-like syndrome involving malaise, myalgia, arthralgia, chills and fever is quite a frequent complication of levamisole treatment. It is occasionally accompanied by a moderate rise in creatine phosphokinase (CPK) levels (Parkinson et al, 1977). Segal et al (1977) reported two out of eight patients with Crohn's disease, treated by levamisole, who developed severe inflammatory arthritis 3-5 months after starting treatment. In the affected cases the arthritis developed during intermittent levamisole treatment. Symptoms developed 12 hours after the first levamisole dose and resolved spontaneously when the three-day treatment period was finished, only to flare up three days later when the next treatment period was started. Although arthritis is an accepted complication of Crohn's disease, in the reported cases the connection between taking levamisole and the occurrence of the joint symptoms was quite striking. A similar phenomenon was observed by Siklos (1977) during levamisole treatment of Beh~et's disease. The Russian authors Sigidin and Bunchuk (1977) reported the case of an 18-year-old girl who developed headache, chest pain, fever and spastic muscle contraction of the extremities a few hours after taking one 150 mg tablet of levamisole. The same pattern of symptoms appeared with increasing severity one and two months later, when the drug was given again. The muscle cramps were considered to be neurogenic. On the third occasion a motor aphasia was also observed.

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CYTOTOXIC TREATMENT In rheumatology, cytotoxic drugs are an accepted treatment for severe SLE, some of the vasculitis syndromes, especially for Wegener's granulomatosis, and for severe RA when other forms of treatment do not control the disease. It now seems clear that cytotoxic agents may be responsible for aseptic necrosis of bone, especially of the femoral head. The initial reports are difficult to interpret as most of the patients were also taking high doses of corticosteroids. Ihde and DeVita (1975) reported four patients with malignant lymphoma who developed femoral head necrosis on combination chemotherapy of mustine (mechlorethamide USP), vincristine, procarbazine and prednisolone. Sweet et al (1976), 1 year later, reported another four patients receiving cyclophosphamide, vincristine, procarbazine and prednisone. However, one of the patients reported by Ihde and DeVita (1975) had not received corticosteroids. In later reports other patients on combination chemotherapy without corticosteroids also developed necrosis of the femoral head (Obrist et al, 1978; Harper et al, 1984; Marymont and Kaufmann, 1986). One of the patients of Marymont and Kaufmann (1986) had received only cyclophosphamide. This complication of combined chemotherapy usually occurs only after 20-42 weeks of cytotoxic treatment, although it has been reported after only 4q5 weeks (Marymont and Kaufmann, 1986). The bones involved include the femoral head, humeral head, femoral condyles, tibial tubercle and scaphoid bone. None of these early reports included patients treated for rheumatic diseases. However, Ansell et al in 1983 reported on a patient with psoriatic arthritis treated by methotrexate who developed bone infarcts and stress fractures, probably due to the methotrexate. Of the patients included in the reports listed above, in only two cases was methotrexate included in the combination chemotherapy (Obrist et al, 1978; Marymont and Kaufmann, 1986). The mechanism underlying osteonecrosis caused by cytotoxic drugs has not yet been clarified. METHOTREXATE

Methotrexate osteopathy occurs during long-term oral maintenance therapy for childhood neoplasm, most commonly acute lymphatic leukaemia (Nesbit et al, 1976; Schwartz and Leonidas, 1984). The first cases were reported by Ragab et al (1970). This syndrome, although uncommon, is very characteristic. Methotrexate osteopathy is characterized by severe limb pains and osteoporosis, which particularly involves the lower extremities. Typically there is a thick dense provisional zone of calcification close to the epiphysis and growth arrest lines develop resembling scurvy. Fractures may occur. The appearance must be distinguished from metastatic disease (Schwartz and Leonidas, 1984). Transverse metaphyseal lucencies beneath the zone of provisional calcification may simulate the changes of leukaemia. Children on long-term methotrexate have normal growth, suggesting that increased resorption of bone is responsible for this osteopenia. This theory is

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supported by the increased urinary and faecal excretion of calcium which is usually present in these children (Schwartz and Leonidas, 1984). Israeli authors have described patients with RA who developed an abrupt onset of extensive rheumatoid nodulosis during methotrexate treatment. The nodules were remarkably large. In addition they observed cutaneous vasculitis in two and Raynaud's phenomenon in one of these patients. All these possessed the HLA DR4 histocompatibility antigen. A cause and effect relationship between methotrexate and accelerated nodulosis in these patients is uncertain, but the authors argue that the arthritis was very well controlled by methotrexate when the onset and rapid growth of rheumatoid nodules occurred. In addition, the nodules regressed after discontinuation of methotrexate therapy, although this might have been an effect of alternative drugs in two of the three cases (Segal et al, 1988). Vasculitis has also been described with this compound (Navarro et al, 1986; Segal et al, 1988). Acute gout may also occur as a consequence of cytotoxic treatment in both malignant and non-malignant diseases, especially where hyperuricaemia occurs (leukaemia, psoriasis) (Martin et al, 1967).

Cyclosporin Cyclosporin may also induce hyperuricaemia and gout (Tiller et al, 1985; Lin et al, 1989). Hyperuricaemia occurs in 30-60% of cyclosporin-A treated patients and gout has been reported in 4-10% (Tiller et al, 1985; Burack et al, 1988). Using renal transplant patients, Lin et al (1989) compared two groups of patients with stable allograft function and serum creatinine concentrations below 265 nmol/l. One group was treated with cyclosporin A and the other by azathioprine. In both groups patients taking diuretics had higher serum urate levels. Nine patients (largely males) developed gouty attacks in the group receiving cyclosporin and diuretics; none of the azathioprine group did so (Lin et al, 1989). It is thought that decreased urate clearance might be responsible for cyclosporin-induced hyperuricaemia (Lin et al, 1989; Noordzij et al, 1990). However, gout develops in 100% of patients taking diuretics at the same time (Noordzij et al, 1990). Weeden (1990) points out that before cyclosporin-induced gout is diagnosed, saturnine gout should be excluded because 5 % of dialysis patients appear to have excessive lead absorption (Weeden, 1990). In the setting of cardiac transplantation, however, Kahl et al (1989) concluded that cyclosporin appears to be the greatest risk factor for gout. One patient has been reported who developed an acute toxic myopathy to cyclosporin (Noppen et al, 1987). Epiphyseal bone pain has also been monitored by Lucas et al (1990).

Azathioprine Azathioprine appears to be remarkably free of side-effects affecting the musculoskeletal system. We were able to find only two cases of myopathy probably attributable to azathioprine therapy (200 mg/day). Myopathy was confirmed by EMG. After stopping azathioprine muscle strength returned to normal within 3 weeks (Clayton, 1974).

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Recently Lossner et al (1989) reported a patient treated with azathioprine (59 g) for possible polymyositis who developed lipid storage myopathy with carnitine deficiency. After treatment with L-carnitine both the biochemical and the morphological features recovered (Lossner et al, 1989).

STEROIDS Cortisone was administered to a patient with RA for the first time in 1948 in the Mayo Clinic, and by 1950 Hench and his co-workers had received the Nobel Prize for developing the drug. However, the place of corticosteroids in the treatment of this disease still remains open to debate (Weiss, 1990). Corticosteroid use in both rheumatic disease and in other situations has been associated with a number of musculoskeletal complications. These include myopathy, steroid bone disease, including both osteoporosis and osteonecrosis, and growth retardation. It has also been associated with joint problems during both systemic use and after local injection.

Arthralgias Arthralgias, and even arthritis, has been reported to be associated with steroid use by a number of authors. It is not clear whether these represent a single entity, whether there are a number of different types of joint disease due to steroids, or whether the problem relates primarily to the underlying diseases for which steroids have been used. Prior to 1965 these patients were classified under two main entities: the steroid withdrawal syndrome (Amatruda et al, 1965) and so-called steroid pseudorheumatism (Rotstein and Good, 1957). However, since 1965 steroid arthralgias have been closely associated with renal transplant and dialysis patients. This association was first reported by Waller et al (1965) in four out of 21 transplant patients. In this series the arthralgias were associated with a reduction in steroid doses. There was also a subsequent high incidence of aseptic necrosis, although this latter involved different joints. Similar series have been reported by a number of authors. These were reviewed by Kahl and Medsger (1986), who associated the problem with marked variations in steroid doses, but could not establish the exact underlying mechanism. These arthralgias affect the knees primarily and the complaints are generally much more severe than any clinical signs would suggest. The pains are most severe at night, but fortunately time limited and all resolve regardless of treatment within a 7-day period (Kahl and Medsger, 1986). There are a number of reports in the literature referring to 'steroid pseudorheumatism'. Slocumb (1953) described myalgias and limb pains occurring after the administration of large doses of cortisone. A similar clinical presentation was termed 'steroid pseudorheumatism' by Rotstein and Good (1957). It is usually more marked in the lower limbs and occurs during dose reduction of the drug (Good et al, 1959; Dixon and Christy, 1980). The exact pathogenesis of this remains unknown, but it usually resolves if the dose of drug is increased again for a short period of time.

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Growth retardation The adverse effects of steroids on growth were observed as early as 1956 (Blodgett et al, 1956), and this effect is seen regardless of the underlying disorder for which the drugs are administered (Kerrebijn and De Kroon, 1968; Lain and Arneil, 1968). It seems likely that the delay in growth is more marked in males (Rees et al, 1988) and this may be due to a delay in onset of the adolescent growth spurt in males. The eventual adult height may be close to the predicted normal (Kerrebijn and De Kroon, 1968), but the delayed growth is a significant additional physical and emotional problem in teenagers required to use steroids (Rees et al, 1988). It has been suggested that steroids suppress the level of circulating growth hormone (Reid, 1989) and thus reduce its anabolic actions on bone. These drugs probably also increase the levels of inhibitor to circulating insulin-like growth factor (Unterman and Phillips, 1985), and in males there is also a significant reduction in circulating testosterone (Reid et al, 1985). Osteoporosis The association between excess corticosteroid and osteopenia was recognized from the time of Cushing's first description of the clinical effects of basophil pituitary adenomas (Cushing, 1932). By the time of Albright in the early forties (Albright, 1943), this association was well established and it was no surprise that similar osteoporosis was described very early as a feature of exogenous steroids (Curtess et al, 1954; Rosenberg, 1958; Livingstone and Davies, 1960). As with osteoporosis resulting from any cause, the disorder is asymptomatic until fractures occur. It has been suggested that steroids affect trabecular bone more than cortical bone (Hahn, 1978; Dempster et al, 1983), and there is a direct correlation between the duration of treatment and the severity of the osteoporosis (Shubin, 1965). Certainly the effects of all the other factors involved in the aetiology of osteoporosis (lack of oestrogen, increasing age, poor nutrition, loss of mobility, etc) are worsened by the use of steroids (Harter et al, 1963). Intermittent steroid regimens diminish but do not prevent the problem.

Pathogenesis Despite half a century of research on the issue, the exact mechanisms by which steroids cause osteoporosis are not fully understood. There are steroid receptors in osteocytes (Feldman et al, 1975) and many of their anabolic processes, such as protein and collagen synthesis, cell growth and production of RNA, are enhanced by steroids in low doses (Dietrich et al, 1979; Gallagher et al, 1984) and inhibited by high doses (Frost and Villanueva, 1964; Peck et al, 1967; Chen and Feldman, 1979; Dietrich et al, 1979). Certainly in the periosteal area the primary effect appears to be inhibitory (Canalis, 1984; Chyun et al, 1984). Similarly, contrasting results on bone resorption have been obtained. Most studies in humans have shown that steroids increase bone resorption (Lund et al, 1985; Reid et al, 1986; Grondwicz et al, 1988), but only where the doses used have been closely

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related to those in human studies has a similar increase been demonstrated in animals (Jee et al, 1972). Other mechanisms proposed in the pathogenesis of steroid osteoporosis include effects on sex hormones, effects on intestinal absorption of calcium, effects on vitamin D metabolism, effects on renal excretion of calcium and phosphorus, and effects on other hormones and mediators including parathormone, 1,25-dihydroxyvitamin D, prostaglandins, cytokines and growth hormone. Consideration of all of these is beyond the scope of this chapter, but they have been carefully reviewed by Lukert and Raisz (1990).

Clinical features Steroid-induced osteoporosis is clinically silent until bone failure occurs. The axial skeleton is most prone to fracture and appears to be more affected in osteoporosis due to steroids (Harter et al, 1963). However, all areas of the skeleton vulnerable to osteoporotic fractures may be affected in patients with steroid-induced disease. Not all patients on steroids suffer structural failure of bone. Premorbid bone mass may be a critical determinant. That in turn is dependent on race, sex and age, as well as, in females, the time from the menopause. Certainly, dose duration and the underlying reason for the use of steroids may also be critical. In severe cases the typical patient is severely kyphotic due to progressive, multiple collapse fractures of the vertebrae. Early on this may be associated with minimal or no symptoms, but chronic back pain, limitation of mobility and respiratory embarrassment may all occur (Adachi and Colton, 1990). There may also be significant morbidity and mortality from limb bone fractures, especially of the femoral neck (Narod and Spasoff, 1985). Generally, the other features of steroid use coexist; centripetal obesity, skin atrophy and purpura and generalized muscle weakness.

Diagnosis Early diagnosis, before the onset of fractures, is essential for steroid osteoporosis (Adachi and Colton, 1990). Patients on high-dose and/or prolonged steroid therapy should be screened consistently for osteopenia. Radiology has been the most widely used diagnostic measure (Michel et al, 1990), but it is relatively insensitive. The more sensitive dual energy radiographic absorptiometry (Sartoris and Resnick, 1989) is becoming more widely available and where possible should be performed, for some authors, at least every 6 months of treatment, so that the rate of change of bone density can be measured.

Therapy The primary treatment for steroid osteoporosis is withdrawal of the drug, reduction of the dose or the introduction of an intermittent dosage regimen where possible. All the known preventive measures for osteoporosis are advisable in chronic steroid users, but the efficacy of these measures is not certain (Adachi and Colton, 1990; Lukert and Raisz, 1990).

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Osteonecrosis

Osteonecrosis or aseptic necrosis of bone is a serious side-effect of corticosteroids. Osteonecrosis was described in the eighteenth century by James Russell, the Professor of Clinical Surgery at Edinburgh (Jones, 1978), but was first associated with steroid administration by Pietrograndi and Mastromarino in 1957. Further reports of this association were soon to follow (Heimann and Freiberger, 1960; Boksenbaum and Mendelson, 1963; Patterson et al, 1964). It is usually seen in the expanded ends of the long limb bones--the head of the femur, the head of the humerus or the distal end of the femur. However, the small cuboidal bones of the carpus or tarsus may also be involved. At each of the common sites of osteonecrosis the necrotic zone is immediately below the load-bearing articular surface of the bone end (Solomon, 1985). Also in these areas the blood supply is probably an endarterial system with no collateral supply (Sevitt and Thompson, 1965).

Pathogenesis The major factor in osteonecrosis is ischaemia. The anatomy of the blood supply is critical in determining the site of the injury. The most heavily loaded segment of the necrotic bone will collapse first, leading to the typical radiological crescent sign. The cause of the ischaemia in steroid treatment is not certain. It is not due to a direct toxic effect of the drugs on bone, but it may be due to fat embolization (Jones et al, 1965; Fisher et aI, 1969; Cruess et al, 1975) or to increased vascular pressure within the affected bone segment (Johnson, 1964; Arlet et al, 1972; Hungerford, 1979).

Clinical features The onset of osteonecrosis is insidious but may present symptoms at any time during the use of steroids. It most commonly presents after 6-8 months (Cruess, 1981) but Vakil and Sparberg (1989) report the onset of symptoms as early as 2 weeks after starting the drugs. There is undoubtedly a relationship with dose and duration of treatment (Cruess, 1977; Zizic et al, 1985), with virtually all cases taking at some stage in the treatment more than 20 mg prednisone or its equivalent daily (Zizic et al, 1985; Vakil and Sparberg, 1989). The disorder usually affects one or two joints, with the femoral head being by far the most likely site. However, regardless of the joint involved, bilateral symmetrical involvement is common (Zizic et al, 1980; Vakil and Sparberg, 1989). The affected joints are usually the site of a chronic boring pain, which is aggravated by movement but which is usually also present at rest. Pain may be absent even in the face of cortical collapse (Weiner and Abeles, 1989), especially in children (Bergstein et al, 1974; Bombelburg et al, 1989). Early diagnosis depends on a high index of suspicion in all patients taking steroids in high doses. Bone scintigraphy is the best method of demonstrating the lesion in the early stages. Reduction in isotope uptake is frequently present before there are any detectable changes on conventional radiographs (Bonnarens et al, 1985). Subsequently, when the radiological appearances are clear and the classic crescent sign is seen (Norman and

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Bullough, 1963), increased isotope uptake is seen. The end result of aseptic necrosis is deformity of the joint surface and the onset of progressive degenerative joint disease (Atkinson et al, 1987). When osteonecrosis is diagnosed at one site, careful observation for other areas of involvement is needed, especially in view of the propensity for symmetrical sites of involvement (Patterson et al, 1964; Merle d'Aubigne et al, 1965; Zizic et al, 1980).

Treatment The best treatment for steroid-induced osteonecrosis is prevention. This means maintaining the lowest daily dose and the shortest possible treatment regimen. However, in many circumstances prevention is not possible. In the early stages core decompression of the affected segment of bone or forage has been recommended (Hungerford and Zizic, 1978; Zizic et al, 1980; Meyers, 1988). The rationale for this has been to relieve the increased intraosseous pressure and perhaps to provide a channel through which bone regrowth can occur (Vakil and Sparberg, 1989). This may be enhanced when a cortical graft is inserted into the channel created (Boettcher et al, 1970; Springfield and Enneking, 1978). Certainly a reduction in the loading of the affected joint is recommended in all cases. This may allow repair without major distortion of the articular anatomy and so avoid the secondary degenerative changes. When collapse of the cortex occurs, most patients, at least when the hip is involved, require replacement arthroplasty (Kenzora, 1985; Vakil and Sparberg, 1989).

Myopathy The adverse effects of corticosteroids on muscle were recognized very early in the clinical use of these agents (Dubois, 1958; Freyberg et al, 1958). This is a general effect of all glucocorticoids, although halogenation at the 9c~ position certainly increases this effect (Afifi et al, 1968).

Clinical features The onset of steroid myopathy is usually insidious, and most commonly affects the pelvic girdle muscles first (Askari et al, 1976). However, myalgias may be an early feature (Ellis, 1985). The time of onset of steroid myopathy is from a few weeks to more than 12 months after the start of systemic use of the drug. The dose and route of administration are important. The higher the dose, the more likely the development of significant muscle weakness (Yates, 1971). Most cases have been associated with doses greater than 40 mg/kg of prednisone or the equivalent (Bowyer et al, 1985) when oral ingestion of the drug has been involved. Particularly florid onset of muscle weakness has been reported after intravenous pulse therapy (McFarlane and Rosenthal, 1977; Van Marle and Woods, 1980; Knox et al, 1986). Any voluntary muscle group may be affected, but involvement of the diaphragm and the laryngeal musculature has been particularly associated with the use of inhaled steroids in asthmatic patients (Williams et al, 1983; Bowyer et al, 1985).

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Diagnosis Js often difficult because muscle weakness is common in many of the rheumatic diseases for which corticosteroids are employed, including RA, SLE and polymyositis (Askari et al, 1976). Muscle enzymes are normal in steroid myopathy, but if the disorder develops in patients with inflammatory muscle diseases it may be very difficult to distinguish which is the main source of a patient's problem at a single point in time. A further confounder may be hypokalaemia, which often results from the use of corticosteroids, and this may be considered to be the more likely cause of muscle weakness (Powell, 1969). Concomitant drug use may also lead to diagnostic difficulty. Phosphate depletion myopathy due to excessive antacid consumption has been reported in conjunction with steroid myopathy. In patients with connective tissue diseases there is often concomitant use of other antirheumatic drugs which can lead to muscle weakness, such as D-penicitlamine or chloroquine.

Diagnosis As noted above, muscle enzymes are normal in corticosteroid myopathy. Askari et al (1976) reported that urinary creatinine levels are elevated, but this probably reflects the extent of the muscle weakness only. Muscle biopsy shows mainly atrophy of type 2B fibres. There is usually no inflammatory infiltrate or muscle necrosis seen (Askari et al, 1976), and the EMG findings may be normal or may show the changes of myopathy (Askari et al, 1976).

Treatment Steroid myopathy responds to the withdrawal of the drug. Where this is not possible, reduction to doses of 10 mg or less of prednisone or the equivalent is helpful and may minimize the muscle weakness. It is advisable to use non-halogenated steroids if at all possible. A programme of musclestrengthening exercises is beneficial (Harber et al, 1985a,b). Muscle weakness is less likely to develop when an alternate-day regimen of administration is employed (Harter et al, 1963). Intra-articular injections of steroids

The value of intra-articular injections of steroids has been well documented, both for RA (Hollander, 1969; McCarty, 1972; Balch et al, 1977; Hardin, 1979) and for osteoarthritis (Hollander, 1970; Balch et al, 1977). Even in juvenile chronic arthritis this technique is largely effective and safe (Allen et al, 1986; Earley et al, 1988; Maigne et al, 1988). Osteonecrosis and secondary degenerative joint damage have been reported after repeated intrasynovial injections, but it is undoubtedly very rare. Hollander et al (1961) reported his experience of 23 500 injections in 8000 patients. Joint damage was felt to have resulted in 79 joints in 62 patients. This experience is confirmed by other studies (Stolzer et al, 1962; Balch et al, 1977), even in children (Sparling et al, 1990). Some authors report a joint pathology quite unlike that of the primary disease in

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repeatedly injected joints (Bentley et al, 1969). The aetiology of this is unclear, but in a recent report Laroche et al (1990) suggested that such osteonecrosis is more likely to be due to systemic hypercorticism than to the local treatment. A neuropathic type of joint disease has been suggested by Gray et al (1981) whereby the normal restriction on movement of a damaged joint is removed by significantly relieving the pain and encouraging further damage. Others have suggested a direct toxic effect on cartilage (Mankin and Conger, 1966), or damage due to induced osteonecrosis. Laboratory investigations, however, have singularly failed to show such adverse effects (Gray et al, 1981). Other mechanical and infective side-effects of local corticosteroid injections are generally recognized more easily. These include joint sepsis, which is very rare (Hollander, 1970), tendon or ligament rupture (Lee, 1957; Sweetnam, 1969), and a transient crystal synovitis resembling a short-lived attack of gout (McCarty and Hogan, 1964; Berger and Yount, 1990). In children, atrophy of subcutaneous tissue around the needle track has been observed (Earley et al, 1988; Job-Deslandre and Menkes, 1990) and seems to be a function of decreasing age and decreasing joint size (Job-Deslandre and Menkes, 1990), but the clinical significance of this does not seem to be very great. More important may be the synovial calcification which occurs in up to 33% of patients (Gilsanz and Bernstein, 1984). This is mostly asymptomatic (Job-Deslandre and Menkes, 1990), but excision surgery was required in at least one case (Jalava et al, 1990). FLUORIDE

There are a number of drugs which are not strictly antirheumatic but which are used to treat disorders which often present to the rheumatologist for treatment. Osteoporosis is certainly such a disease and the iatrogenic problems of fluoride are included here. Fluoride has been used for more than 20 years to combat the osteopenia of involutional osteoporosis (Cass et al, 1966). There is little doubt that sodium fluoride increases the thickness of bone trabeculae (Eriksen et al, 1985) and that it increases the bone mineral density of the spine, as measured by its ability to block ionizing radiation (Riggs, 1984; Riggs et al, 1990). However, there is also a significant increase in osteomalacia (Cass et al, 1966), even when vitamin D is added to the treatment regimen (Compston et al, 1980), and there is increasing evidence that sodium fluoride does not diminish the rate of fractures of the spine (Riggs et al, 1990) or hip (Hedlund and Gallagher, 1989; Riggs et al, 1990). Many patients taking sodium fluoride experience severe pains in the lower limbs. These are intermittent but each episode is often associated with erythema of the affected limb and may last one to two months. The pain may be so severe as to require the use of crutches. There is some evidence that these episodes may represent incomplete fractures of the long bones consistent with those seen in osteomalacia, but this remains to be proven (Heaney et al, 1989; Riggs et al, 1990).

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