penicillamine

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long-term therapy, the half-life rises to 4–6 days, ... penicillamine having an inhibitory action on T-helper .... SASP (51%) compared to penicillamine (40%); life.
British Journal of Rheumatology 1997;36:104–109 DISEASE-MODIFYING DRUGS SERIES SERIES EDITOR: T. PULLAR

PENICILLAMINE R. MUNRO and H. A. CAPELL Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Castle Street, Glasgow G4 0SF

P has been used in the treatment of rheumatoid arthritis for more than 30 yr [1]. Over this period of time, it has shown itself to be an effective disease-modifying agent, improving many of the clinical and laboratory indices of disease activity. However, in common with many slow-acting antirheumatic drugs (SAARDs), these benefits have to be balanced against potentially serious side-effects. As more second-line agents become available, the experience of individual rheumatologists with each drug will be less and the place of penicillamine in the therapeutic repertoire may become less clear.

which penicillamine acts as a disease-modifying agent in the treatment of rheumatoid arthritis remains unclear. The thiol group on penicillamine and oxidative reactions involved in the metabolism of penicillamine appear to be central to all the proposed modes of action. In vitro studies have shown a potential immunomodulatory effect as well as direct actions at sites of inflammation. Initially, it was thought that penicillamine acted by dissociating the bonds binding the macromolecules of IgM that made up rheumatoid factor [7]. This theory can be discounted since the concentration of penicillamine required is not achieved in vivo using conventional doses, and there is no correlation with reduction in rheumatoid factor and clinical efficacy [8]. The reduction in globulins is probably due to penicillamine having an inhibitory action on T-helper cell-mediated B-cell expansion and activation rather than a direct action on B cells [9]. In the presence of copper, penicillamine undergoes oxidation of its thiol group to form H2O2; this molecule has a direct inhibitory effect on T-helper cell function and possibly also natural killer T cells [10]. Penicillamine may also act at the site of inflammation by impairing fibroblast proliferation and thus pannus formation [11]. Again, this occurs due to H2O2 production in the presence of copper. Studies have also shown that penicillamine may scavenge some of the free radicals release by activated neutrophils [12] and inhibit the granular enzyme myeloperoxidase, thus reducing local tissue damage [13].

PHARMACOLOGY Structurally, penicillamine is an amino acid with a thiol side chain (Fig. 1). Penicillamine can be prepared by hydrolytic degradation of penicillin or chemically synthesized. It can exist as two enantiomers:  and . However, only the  type is clinically useful due to excessive toxicity of the  type. Oral absorption is good in fasting subjects with a bioavailability of 40–70% [2]; however, availability is severely reduced if penicillamine is taken in conjunction with iron preparations, antacids or food [3, 4]. Within the body, penicillamine is rapidly oxidized to form various disulphides, the most important of these are with proteins, cysteine, homocysteine and penicillamine itself [5]. The serum half-life of a single dose of penicillamine is 2–4 h. In patients on long-term therapy, the half-life rises to 4–6 days, although traces of penicillamine can be detected in the serum weeks after cessation of therapy, presumably due to mobilization of a tissue-bound pool [6]. Clearance of the disulphides is mainly in the urine, although a substantial proportion is excreted in the faeces [5].

PLACEBO-CONTROLLED TRIALS There have been a number of placebo-controlled studies documenting the efficacy of penicillamine in the treatment of rheumatoid arthritis, these are summarized in Table I. The first substantial double-blind placebo-controlled trial was reported by the Multicentre Trial Group [14] in 1973. They used doses of penicillamine which would now be considered excessively high (1.5 g/day) over a 12 month period. The results for the penicillamine group showed a mean reduction of 050% for pain and articular index, a 34% reduction in the erythrocyte sedimentation rate (ESR) and over 80% reduction in morning stiffness. There was also 30% improvement in grip score and 12% improvement in haemoglobin. All these changes were at a significant level (P Q 0.01–0.05) when compared to the placebo group. However, they noted a relatively

MODE OF ACTION As is the case with other SAARDs, the method by

*SH NH2 5 5 (CH3 )2 C- - - - - - - -CHOOH F. 1.—Structure of penicillamine (*denotes thiol side chain).

Submitted 17 June 1996; revised version accepted 20 June 1996.

= 1997 British Society for Rheumatology 104

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MUNRO AND CAPELL: PENICILLAMINE TABLE I Placebo-controlled studies

response to treatment. At 24 weeks, the response rates were 27 and 65%, respectively. These improvements were mirrored in a composite activity score consisting of ESR, grip strength, duration of morning stiffness and active joint count. There were suggestions from non-placebo-controlled studies that even lower doses of penicillamine, as low as 125 mg/day, may be effective. Williams et al. [17] performed a placebo-controlled study using penicillamine doses of 125 and 500 mg. Their results were atypical in that they found 125 mg no better than placebo, and 500 mg of only modest clinical benefit. Interestingly, it was the patient’s assessment scale that showed the most significant improvement. They commented on the marked improvement in the first 6 weeks of their trial in all three groups, including the placebo group, and stressed the importance of a control group, particularly in short-term clinical studies. It should be noted, however, that 45% of the placebo group were on low-dose prednisolone with 26–34% of the penicillamine groups also receiving steroids.

Authors

Year No. of patients entered Maximum dose (mg) Duration of study (weeks) Withdrawal rate (%) Randomized and double blind Comments

Multi-centre Trial group [14]

Dixon et al. [15]

Shiokawa Williams et al. et al. [16] [17]

1973

1975

1977

1983

105

121

179

225

1500

600/1200

600

125/500

52

24

24

30

42

29/45

34

20/29

Yes Yes Yes Yes High dose No Response Lower with high difference rate: 44% dose no drop-out in efficacy at 12 better rate between weeks and than high and 65% at placebo low doses 24 weeks

high drop-out rate with only 58% of the penicillamine group completing a year of treatment compared to 72% of the placebo group. Dixon et al. [15] addressed the question of dose in their 24 week study reported in 1975. They found no significant difference in efficacy between doses of 600 and 1200 mg/day, and that both were better than placebo. There was a mean reduction in ESR of 20–25 mm/h in the penicillamine groups. There was also a significant improvement of almost one point on a four-point pain scale in both treatment groups. There were no significant differences between any of the groups for physician assessment of disease activity or duration of morning stiffness. Again, there was a high drop-out rate in the penicillamine group which appeared to be dose dependent: 26% of the 600 mg group stopped treatment due to adverse reactions compared to 40% of the 1200 mg group. Similar results were achieved by Shiokawa et al. [16] in 1977 when they compared doses of 600 mg of -penicillamine with a group designated as placebo, although on average this group was receiving 30 mg of penicillamine a day. Differences between the two groups were apparent at 12 weeks with 13% of the control group and 44% of the treatment group assessed by their physician as having either a good or excellent

COMPARISON WITH OTHER AGENTS There have only been a few studies comparing penicillamine with other second-line agents. The studies performed have relatively short follow-up periods and often lack the required power to show a significant difference between two active agents (Table II). None of the studies contained the minimum of 170 patients per group recommended by Felson et al. [18] to show a difference between second-line agents. One of the largest studies was a comparison of sulphasalazine (SASP) vs -penicillamine in 200 patients at median doses of 2.5 g and 500 mg, respectively [19]. After 2 yr, more patients remained on SASP (51%) compared to penicillamine (40%); life table analysis showed this difference not to be significant. Although there was a trend for patients to have a greater improvement in clinical and laboratory indices in the penicillamine group, these changes were not significant at 2 yr. A smaller study with 88 subjects, comparing penicillamine 750 mg/day with auranofin 6 mg/day over 12 months, found that patients tended to improve more on penicillamine [20]. At 12 months, there were significantly greater improvements in grip strength and swollen joint count (P Q 0.003) in the penicillamine group compared to the auranofin group.

TABLE II Comparative studies Author

Year

Drugs

Patient number

Double blind and randomized

Comment

Hochberg et al. [20] Gibson et al. [27] Thomas et al. [25] Bunch et al. [22] Capell et al. [19] Paulus et al. [24] Berry et al. [23]

1986 1976 1984 1984 1990 1984 1976

-pen/auranofin -pen/myocrisin -pen/myocrisin -pen/HCQ/combination -pen/SASP -pen/azathioprine -pen/azathioprine

88 87 50 54 200 206 65

Yes Not blinded Yes Yes Yes Yes Single blind

Penicillamine more effective and toxic No difference No difference Penicillamine more effective No difference No difference No difference

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There were also trends for other markers of disease activity to improve more in the penicillamine group, but these did not reach significance, probably due to the numbers involved. Other studies comparing penicillamine to hydroxychloroquine (HCQ) [21], azathioprine [22, 23] and i.m. gold [24, 25] showed little difference between each agent, although only one of the studies had more than 46 patients entered into each group. The results of a large meta-analysis by Felson et al. [18] reinforce the above findings. They combined the results of 66 studies of 117 treatment groups and judged efficacy on the basis of improvements in ESR, grip strength and a joint count. Their results showed that penicillamine was significantly more effective than oral gold (P Q 0.0001), but there was no detectable difference in efficacy between penicillamine and methotrexate, i.m. gold or SASP. Meaningful results from X-ray studies have been hampered by the small numbers of subjects enrolled. A study comparing penicillamine with HCQ in 43 patients showed significantly less progression of erosions in the penicillamine group at 1 yr [26]; however, this difference was not maintained in the second 12 months so that by the end of 2 yr the groups were indistinguishable. In a study comparing i.m. gold with penicillamine, there were pairs of X-rays available for 55 patients at the end of 1 year and 44 patients at 2 yr [27]. There appeared to be little progression of erosions over the 2 yr in the penicillamine group compared to a mean deterioration of over 20% in the gold group, between-group comparison at 2 yr favoured penicillamine (P Q 0.02). However, it should be noted that at the outset the gold group was initially much more erosive with a mean erosion count of 33.4 compared to 19.8 in the penicillamine group, and as such the two groups were not truly comparable. In common with most SAARDs, there are little long-term efficacy data for penicillamine. Some information is available from a 5 yr study which followed 675 patients treated with either penicillamine, gold or SASP [28]. Although more patients stayed on gold (36%) compared to penicillamine (22%) or SASP (26%), there were no significant differences between the groups. All three agents were equally efficacious. The greatest improvements in measures of disease activity were seen in the first year and these improvements were generally maintained over the 5 yr period, although there was a small but significant rise in the Health Assessment Questionnaire (HAQ) score after the first year. The commonest reason for discontinuation of therapy in each group was side-effects. An earlier study by Pincus et al. [29] reached a similar conclusion regarding the duration of therapy and reasons for stopping penicillamine. They, however, included more SAARDs and found that patients tolerated methotrexate significantly better than any other SAARD, including penicillamine. After 5 yr, 62% of patients remained on treatment with methotrexate compared to 20% of the penicillamine group.

COMBINATION WITH OTHER SECOND-LINE AGENTS Trials of combination therapy that include penicillamine have had mixed results and are difficult to interpret due to the very small numbers involved. There is no evidence that the combination of penicillamine and anti-malarials is any more beneficial than penicillamine alone [30]. Surprisingly, one study suggested that patients on combination therapy did less well than those taking either agent on its own, although there were less withdrawals due to side-effects in the combination group [22]. The results of the combination of SASP and penicillamine are inconclusive. A small study conducted by Taggart et al. [31] with 30 patients over 6 months found that there was a slightly better response rate in the SASP/-penicillamine group compared to SASP alone at the expense of greater toxicity. Unfortunately, there was no group treated with penicillamine alone for further comparison. A different approach to the use of combination therapy is to add a second agent to patients tolerating, but not responding to, therapeutic doses of penicillamine. One such study added treatment with 2 g of SASP to 10 patients not responding to up to 750 mg of penicillamine [32]. Overall, the treatment was well tolerated with five patients classified as having a good response and a further three having a partial response. Combination therapy with i.m. gold has been more promising, despite the obvious concerns regarding its similar toxicity profile. In a 6 month double-blind study comparing each agent singly against the combination of the two, the patients on combination treatment appeared to respond at 4 weeks vs 8 weeks for those on monotherapy, although this difference is probably not relevant [33]. At 6 months, there were no significant differences in efficacy or toxicity in all three groups. Bitter [34] reported the results of two trials looking at combination therapy in patients who had responded inadequately to gold or penicillamine alone after 1–2 yr of treatment. It was found that 75% of patients staying on combination therapy improved significantly compared to 7% of those who stayed on monotherapy. The drop-out rates due to toxicity were similar in each group. To date, no combination therapy that includes penicillamine has become part of mainstream rheumatological practice. This is probably due to continuing concerns regarding increased toxicity for only a modest potential benefit. TOXICITY Drug toxicity is the commonest cause for discontinuation of penicillamine therapy, with up to 45% of new starts eventually discontinuing for this reason [29]. Toxicity can appear at almost any time during treatment and although there is a dose relationship to the frequency of side-effects, even low doses of penicillamine can lead to potentially fatal adverse reactions. It is, however, important to put this into

MUNRO AND CAPELL: PENICILLAMINE TABLE III Side-effects occurring with penicillamine

System Mucocutaneous Gastrointestinal Renal Haematological Autoimmune Lungs Pregnancy

Occurrence rate (%)

Side-effects

10–20

Mouth ulcers, urticarial skin rashes, pruritis, lichen planus and pemphigus 10–20 Dysgeusia and nausea, rarely abnormal liver function 10–15 Proteinuria, glomerulonephritis and Goodpasture’s syndrome 5–10 Thrombocytopenia, leukopenia and aplastic anaemia Uncommon Myasthenia gravis, polymyositis, pemphigus, SLE and Goodpasture’s syndrome Rare Bronchiolitis obliterans [53] Fetal connective tissue abnormalities

context: an analysis of drug toxicity in RA showed penicillamine to have a very similar toxicity index to methotrexate, although HCQ was significantly less toxic [35]. The most important side-effects are detailed in Table III. The most common reason for discontinuing penicillamine is mucocutaneous reactions, including mouth ulcers, urticarial and pruritic skin rashes [36]. Altered taste (dysgeusia) is another important early side-effect that usually settles if patients are able to persist with treatment [37]. Renal complications, particularly the development of proteinuria, are well recognized as with injectable gold. The most common cause of the proteinuria is an immune complex-mediated glomerulonephritis [38]. Regular monitoring of urinary protein by dipstick analysis should lead to early detection and if significant proteinuria is confirmed then cessation of therapy. A report of 33 patients with penicillamine-induced

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proteinuria demonstrated that it resolved in all patients by 21 months (mean of 8 months) after discontinuation of therapy [39]. Haematological toxicity causes up to half of the deaths associated with penicillamine (Committee on Safety for Medicines, personal communication) and regular blood monitoring is essential. Fatalities are rare and are mostly due to the development of neutropenia or marrow aplasia which may occur at any time during therapy. More common, but generally less serious, is thrombocytopenia which is dose related and is thought to occur due to direct megakaryocyte toxicity [40]. The platelet count generally recovers in a few weeks if the drug is discontinued. In cases of mild thrombocytopenia in patients with a good response to treatment, dose reduction may be appropriate. A number of autoimmune disorders can occur as a consequence of penicillamine usage despite the noted immunomodulatory effects of the drug. These include myasthenia gravis [41, 42], polymyositis [43], Goodpasture’s syndrome [44], systemic lupus erythematosus [45] and pemphigus [46]. These conditions can be life threatening with at least one death recorded due to polymyositis [47]. However, prompt recognition of the problem and discontinuation of penicillamine usually lead to a full recovery. Another rare side-effect of penicillamine is mammary hyperplasia; identification of the problem and immediate cessation of penicillamine in such cases is mandatory [48]. There is no information on whether penicillamine is present in breast milk, but rarely it can cause connective tissue problems in the fetus if the mother is being treated with penicillamine [49]. There have been attempts at identifying groups of patients at increased risk of developing side-effects. Neither HLA typing [50, 51] nor assessment of sulphoxidation status [52] has proved helpful in a practical sense in predicting which patients will develop toxicity on penicillamine.

TABLE IV Management of side-effects Side-effect Mucocutaneous event Loss of taste Nausea and vomiting Fall in WBC to Q4 × 109/l Fall in platelet count to Q150 × 109/l Proteinuria (trace) Proteinuria (one + or more) Haematuria Abnormal liver function tests

Management Withhold penicillamine and look for an alternative cause; if none found, then discontinue penicillamine. Beware of pemphigus-like rash which is a definite indication for permanent withdrawal and dermatological advice should be sought Reassure patient that this is a transient phenomenon and that taste will return Decrease or hold dose and look for alternative causes. This usually settles as treatment is continued, although occasionally penicillamine has to be withdrawn Unusual, but if confirmed then stop penicillamine Withhold penicillamine and if confirmed consider re-starting at a lower dose with close monitoring. If there is a precipitous fall to Q10 × 109/l, then specific treatment may be necessary and penicillamine should be withdrawn permanently No action required Screen for urinary infection and quantitative 24 h protein loss. If q0.5 g/24 h, then withdraw penicillamine. If the proteinuria settles, it may be possible to re-start penicillamine with close monitoring Continue treatment and screen for possible causes. Consider drug-induced Goodpasture’s syndrome Stop penicillamine and investigate for other possible causes. If no other explanation found, then withhold penicillamine permanently

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DRUG INTERACTIONS The most common drug interactions with penicillamine are due to its chelating properties. In particular, iron preparations and antacids containing either magnesium or aluminium can reduce the absorption of penicillamine by as much as 66% [2]. If these medications are necessary, then they should be taken 12 h before or after penicillamine. There has been some evidence that concurrent administration of penicillamine with HCQ or indomethacin [54] can increase the plasma concentrations of penicillamine, although the clinical relevance of this is unclear. PRACTICAL PRESCRIBING The indications for penicillamine in the treatment of RA are the same as for any of the other second-line agents, i.e. a combination of inadequate symptom relief with non-steroidal anti-inflammatory drugs (NSAIDs) and ongoing inflammatory joint disease. Penicillamine is generally considered to rank in efficacy along with gold and methotrexate, and should be used possibly after a trial of a potentially less toxic second-line agent such as SASP and anti-malarials. As there is some evidence that side-effects are more common at higher doses, it is customary to start with a dose of penicillamine of 125 mg daily and increase the dose every 4 weeks by 125 mg, aiming for a target daily dose of 500 mg. Patients are advised that it can take 3–6 months before the full benefit may be apparent. If there is inadequate clinical response at 18–24 weeks, the dose can be increased up to 750 mg and maintained at this for a further 12 weeks. Again, if the response is inadequate, but the patient is tolerating the drug well, further increments up to 1 g can be made before treatment is abandoned. Initially, the haemoglobin, white cell count, platelets and urinalysis should be monitored fortnightly until a stable dose is achieved, thereafter monitoring can be reduced to every 4 weeks. A monitoring card for recording the results is useful along with an information sheet for the patients and family doctors detailing the rational for treatment, along with dosage recommendations and potential side-effects. The most commonly encountered problems with penicillamine treatment and the suggested course of action are shown in Table IV. CONCLUSIONS Despite the adverse effects which have been detailed, penicillamine remains an effective drug in patients with rheumatoid arthritis. In the interests of their patients, rheumatologists should make every effort to remain acquainted with all the available modalities to ameliorate this common disabling disease— penicillamine is certainly one such option. R 1. Jaffe IA. Comparison of the effect of plasmapheresis and penicillamine on the level of circulating rheumatoid factor. Ann Rheum Dis 1963;22:71–6.

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37. 38. 39. 40. 41.

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46. 47. 48. 49. 50.

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53. 54.

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