Ann Rheum Dis: first published as 10.1136/ard.42.4.474 on 1 August 1983. Downloaded from

Annals ofthe Rheumatic Diseases, 1983, 42, 474-475

Conference report Heavy metals and arthritis

The fourth annual day conference in the series had been shown to be effective both in clinical terms 'Growing Points in the Treatment of Arthritis' was and in biochemical terms as judged by a rising his- held at the Granby Hotel, Harrogate, on 7 April tidine and total serum sulphydryl and a falling plasma 1983. It was devoted to the topic 'Heavy Metals and viscosity and C-reactive protein. Trien, a metal Arthritis' and attracted an audience of about 100, chelating drug that is used in an alternative to both physicians and chemists. Professor Verna D-penicillamine in the treatment of Wilson's disease Wright and Dr Howard Bird acted as chairmen. but which does not contain an -SH group, was ineffec- Dr P. J. Sadler (Department of Chemistry, Birkbeck tive. By contrast captopril, an angiotensin-converting College, University of London) reviewed current enzyme inhibitor with a structure similar to knowledge of the chemistry ofzinc, copper, and gold. D-penicillamine (including an -SH group) caused Metals are far from the inert structures envisaged by improvement comparable to that from some physicians. The reactivity of the metal or D-penicillamine. It was argued the mode of action of metallic ion is an amalgam of the charge present on D-penicillamine was more likely to lie with its -SH the ion, the co-ordination geometry, and its mobility group than with its metal chelating properties. in biological systems. In addition, consideration had Dr A. J. Kennedy (Roche Products Ltd) discussed copyright. to be given to other elements such as the sulphur the use of the Lipsky-Ziff assay system for the study atom present in D-penicillamine and the potential for of in-vitro lymphocyte function from animals treated reduction or oxidation in the tissues. Metals in drugs with D-penicillamine and other drugs. A variety of were in equilibrium with metal-containing enzymes drugs that might have a penicillamine-like action had such as cytochrome oxidase (which contains copper), been studied in this system and some novel com- and these enzymes could exist in a variety of forms. pounds that appeared effective were being con-

The synthesis of metallothionines, present in all tis- sidered for clinical trials. Many of these contained http://ard.bmj.com/ sues, could be regulated by trace amounts of metal sulphydryl groups. The intimate role of metals, ions such as Ca", Zn+, and Au... and this in turn including copper, in this system was stressed by the might explain the mode of action of metal containing chemists. drugs. Dr R. J. Ward and co-workers (Northwick Park Harrow) then discussed their serial estimations of Copper and zinc copper and zinc in patients with rheumatoid arthritis being treated with second-line drugs. Patients had The remainder of the morning session considered been treated with aurothiomalate, auranofin, on September 28, 2021 by guest. Protected copper and zinc. Dr D. Grennan (Manchester) D-penicillamine, or hydroxychloroquine. The raised complemented these theoretical considerations with plasma copper fell before a more gradual rise in the a clinical evaluation of serum copper, zinc, and lowered plasma zinc as the patients came under caeruloplasmin in patients with active rheumatoid chemical control. It was argued that even gold com- arthritis, osteoarthritis, and in controls. Serum levels pounds were working through copper metabolism. of copper and caeruloplasmin were significantly After a lunch break the afternoon programme higher and zinc significantly lower in osteoarthritis moved from copper and zinc to a consideration of than in controls. Copper and caeruloplasmin were iron and gold. still further raised in the rheumatoid group compared with the other 2 groups, and zinc was lowered in the Iron and gold rheumatoid group, though not more so than in osteoarthritis. Iron-free radicals and rheumatoid synovitis were Dr J. S. Dixon, a biochemist (Harrogate), then considered by Dr D. R. Blake (Birmingham). He compared the use of D-penicillamine, trien, and cap- argued, using in-vitro, in-vivo and animal model topril in active rheumatoid arthritis. Penicillamine evidence, that iron might exacerbate rheumatoid arth- 474 Ann Rheum Dis: first published as 10.1136/ard.42.4.474 on 1 August 1983. Downloaded from

Conference report 475 ritis through the formation of the highly inflamma- In an integrated presentation from Glasgow, a bio- tory hydroxyl radicals. In-vitro, ferrous iron, but not chemist (Dr D. Brown) and a physician (Dr D. ferric, promoted hyaluronic acid degradation, and Lewis) evaluated redox parameters in patients this reaction was inhibited by iron chelating drugs, receiving auranofin, aurothiomalate, or placebo. The OH' scavengers, and caeruloplasmin. In-vivo the fer- choice of superoxide dismutase activity (SOD), roxidase activity of caeruloplasmin was significantly plasma and lysate thiol (PSH and LSH) concentra- depressed in joints with rheumatoid synovitis, and in tions, and caeruloplasmin oxidase (CP) activity as animals desferrioxamine, an iron chelating agent, assays that reflected both intra- and extracellular free inhibited the chronic phase of some models of radical activity was explained by Dr Brown. Dr Lewis inflammation. A trial of desferrioxamine in man had studied 90 patients with rheumatoid arthritis and might be of interest in confirming the hypothesis. classified them as 'responders' and 'nonresponders' Brief clinical and immunological papers on gold in the 3 treatment groups. Responders showed an compounds then followed. Dr J. Mackenzie (Peter- initial further deterioration in SOD and LSH levels borough) described her clinical success in the use of followed by return to more normal levels. The PSH sodium aurothiomalate in a dose of only 10 mg and CP did not show the same early change but weekly compared with the more conventional 50 mg returned to more normal levels after 24 weeks in the weekly at the start of treatment. She argued that trials responders. 'Nonresponders' showed no such that used the conventional higher dose of aurothio- change. Gradual clinical improvement appeared to malate as a comparative product provided too high be preceded by an initial proinflammatory response. an incidence of side effects. Dr S. J. Hopkins (Man- In the final paper Dr R. J. Horton (Smith, Kline chester), an immunologist, described his work on and French) outlined the comparative safety and effi- lymphocyte activities in-vitro with gold sodium cacy of auranofin and parenteral gold compound, thiomalate. Various factors affected activity and drawing on a large computer-based data bank from kinetics in mouse lymphocytes, though the relevance studies all over the world. Reference was also made of this test system to human rheumatoid synovitis was to poster demonstrations by Keegan and Cole, who questioned by the audience. compared oral and injected gold in patients with copyright. Dr S. R. Rudge's study from Nottingham was rheumatoid arthritis, and Hunt and Holt whose based on the in-vivo dissociation of sodium poster described an open dose ranging study of aurothiomalate in rheumatoid arthritis. Radio- auranofin in rheumatoid arthritis. labelled work had suggested an early dissociation of The next conference in the series will convene on 5 injectable gold in the body into thiomalate and gold. April 1984, and suggestions for topics, clinical or An assay for free thiomalate had been developed and laboratory, would be welcomed by the organiser, Dr

recovery rates after injection in patients with H. A. Bird. http://ard.bmj.com/ rheumatoid arthritis suggested that the thiol was freely available during early therapy, the gold less so. The possible contamination of commercially avail- able sodium aurothiomalate with some free thioma- Royal Bath Hospital, H. A. BIRD late and the implication of this for the results was Cornwall Road, discussed. Harrogate HG1 2PS on September 28, 2021 by guest. Protected