Factors in gold dosage and toxicity in rheumatoid arthritis.

Since the discovery of cortisone, the gold treatment of rheumatoid arthritis has been overshadowed by the dramatic action of this new remedy. As both cortisone and ACTH have been shown to be capable of maintaining their effect in a proportion of cases with appropriate maintenance dosage, and particularly as cortisone can be given by mouth, it would appear at first sight that there can no longer be a place for chrysotherapy in the treatment of this group of disorders. Though this may come to be the position in the future it certainly is not so at present, and until supplies of these newer agents are adequate to serve the needs of all rheumatoid sufferers, gold will continue to be used. It is essential, therefore, that it be used to the greatest advantage and any means by which toxicity can be reduced without impairment of therapeutic benefit must be carefully investigated. The ability of gold to induce remissions in rheumatoid arthritis has been shown by controlled therapeutic trials (Ellman and Lawrence, 1938a, b; Ellman and others, 1940; Fraser, 1945; Kling and others, 1949), but the high relapse rates (Egelius and others, 1952) show that the effect at least with present therapeutic dosage is not curative, relapse being particularly frequent when low dosage has been used (Short and others, 1948; Browning and others, 1947). Owing to the very slow excretion rate of gold, however, relapses may not occur for some considerable time, and even after an observation period of 9 years patients treated with gold have been found to fare better than those receiving other methods of treatment (Kling and others, 1949). That the effect of gold is proportional to dosage has been shown in animals by Sabin and Warren (1940), and in man by Ellman and others (1940). Some workers have suggested that dosage of the order of 50 mg. weekly may be as effective as a larger dose (Freyberg and others, 1941 ; Comroe, 1945), but they have produced no statistical evidence in support of their claim. The indications from animal experiments are that the optimum total dosage is of the order of 100 mg./kg. (6 g./60 kg.) given over the shortest possible time. It would appear, therefore, that successful gold treatment depends on administering a maximum dosage of gold whilst at the same time avoiding its more dangerous side-effects. Before discussing how this may best be achieved, it is necessary to consider certain pharmacological properties of gold. Gold compounds injected intramuscularly are slowly absorbed from the site of injection, attaining, with normal therapeutic dosage, a maximum blood level of up to 2 mg./100 ml. of plasma by the 4th weekly injection. After stopping treatment the blood level slowly falls; reaches half its final level by the 9th week, but still continues to show detectable amounts at the end of the 4th month. Gold can be detected in the urine up to 10 months after stopping treatment (Freyberg and others, 1941; Hartung and others, 1941), and has been discovered in the tissues after periods of up to 3 years. In the blood, gold is combined with the plasma proteins (Freyberg and others, 1944). This gold-protein complex is a chemical compound and does not release gold ions in solution (Libenson, 1945). As colloids and other substances of high molecular weight present in the plasma can pass out of the circulation only through damaged capillaries, they tend to become concentrated at a site of induced inflammation (Menkin, 1936). It follows that gold in its combination with protein will not readily pass into the tissues except at a focus of inflammation. In a patient with active rheumatoid arthritis the gold will thus pass largely into the inflamed synovial tissues, and the concentration in such tissue has, in fact, been found to be some 18 times as great as in, for example, the skin (Bertrand and others, 1948). Thus, so long as there is active exudation into the diseased tissues, the danger of toxic effects in the skin, mucous