TREATMENT OF RHEUMATOID ARTHRITIS WITH GOLD

406 can use them, and if even this is others, Smith et al.3 sought to explain differences in be rod a held in the possible they operated by response by variations in the rate of excretion of gold in mouth. Quite ambitious pictures have been painted with the urine. Measurements of excretion led them to the a brush held in the mouth. conclusion that a predetermined dosage may fail to be Such patients can be treated at home provided that effective because the patient excretes gold unduly rapidly, can be and the to about the or may quickly lead to toxic effects if excretion is less they supervised, ability go outside world in general and home in particular provides than normal. Differences in the duration of remission are a greater boost to their morale than anything else. There due, they find, to the same causes. Treatment must be are some differences of opinion on how this is best designed to achieve an effective accumulation of gold in achieved. Undoubtedly, if a patient has a tracheotomy the body by giving a weekly dose which exceeds the in the acute stage it should be closed when he recovers amount excreted by the kidneys and by other routes, enough power to breathe spontaneously for several hours Normally patients receiving weekly injections of 25 mg, a day. But it is less certain whether tracheotomies should of gold secreted about a seventh of this amount in the be closed in those who remain permanently with comsucceeding week; one patient excreted 28% of each dose plete, or very severe, respiratory paralysis and can in the week after injection, and did not respond until the breathe spontaneously for only a few minutes. One policy dose was raised to a point at which the excretion-rate amounted to only 14%. is to close the tracheotomy and treat the patient in a tank respirator; the advantage of this lies in the reduced risk of In routine practice it is not feasible to regulate the pulmonary infection. The alternative is to maintain the dosage of gold by measuring its excretion, and Smith et al, tracheotomy, giving artificial respiration by intermittent suggest a method whereby the patient’s response to positive pressure; the danger of pulmonary infection ma) treatment can be used as a guide. After 12 weeks on a be counterbalanced by the greater ease of treating this, standard weekly dose, patients are divided into those since secretions can so readily be aspirated from the chest. showing some improvement and those whose conditionis The question is still unresolved, but possibly the decisive unchanged. The former continue to receive the same factor will be mobility. Although it its possible to travel weekly dose until they have been in remission for 1-2 extensively in a tank respirator it is by no means easy to weeks, and are then given a maintenance dose at longer ’ do so, and air travel is virtually excluded. With interintervals. The unresponsive group proceed to a higher mittent positive-pressure respiration, on the other hand, weekly dose, and to a second division at which the a respirator which has a 12-volt motor, such as the favourable reactors join the maintenance programme and Radcliffe Respiration Pump, can be housed with an the remainder move to a still higher dose. Maintenance accumulator that will last 24 hours on a shelf attached to treatment is continued for an arbitrary period of 8 months, the back of a wheelchair. This enables the patient not only When this method was used, 82% of patients had a to get about in the neighbourhood of his home or hosremission; the corresponding figures for two types of pital, but even to visit places of entertainment. The ease standard course were 54% and 66%. Smith et al. hope with which such patients can travel by air has been that an even higher proportion of remissions will be demonstrated when Britons who have contracted polioachieved as refractory patients receive progressively more myelitis in Africa or the Far East have been flown to England. intensive treatment. When a patient with respiratory weakness leaves hosSome years ago Lawrence4suggested a rather similar pital it is essential that he should know where to turn for flexible dose scheme in which a fall in erythrocyteimmediate help if he gets into difficulties of any kind. sedimentation rate (or, better, in fibrinogen level) is In most parts of the country there is a service for bringing used as a warning that the weekly dose of gold should be to hospital people with acute respiratory paralysis, and reduced. This is consisterit with the common observausually these teams are most suitable for giving assistance tion that toxic reactions follow quickly on a good clinical also to more chronic patients. response. Lawrence held that the distribution of gold TREATMENT OF in the body was more important than its total concentraRHEUMATOID ARTHRITIS WITH GOLD tion, believing that while the sedimentation-rate is high THIRTY years after the first account of the use of gold the skin and other potential sites for toxic effects are salts in the treatment of rheumatoid arthritis 1their from high concentrations of gold by the protected place is still not firmly established. Several careful readier diffusibility of the metal in areas of active inflamstudies have provided weighty evidence that gold can mation and increased capillary permeability. When the induce a remission; but their conclusions have not been disease becomes less active this mechanism no longer universally accepted, and the question is now being operates and toxic reactions become more likely. B submitted to the test of a statistically controlled clinical adopting a flexible programme of dosage Lawrence trial in this country. reduced the incidence of stomatitis; and lesions of both Those who accept that gold is effective have to choose mouth and skin became mild and transient rather thar, a course of treatment calculated to produce a good persistent and distressing disabilities. Both Smith et a! response with the minimum risk of toxic effects. The and Lawrence are prepared, in patients who have ha commonly used homoeopathic doses, unlikely either to toxic signs, to continue treatment with gold at a suitably influence the disease or to produce signs of toxicity, are adjusted dose level. After mild toxic reactions h clearly not the solution; and a report from Philadelphia3 subsided Smith et al. encountered subsequent undesirable supports the belief that the dosage of gold salts should reactions no more often than in patients treated with be tailored to the needs of the individual patient. Starting standard courses. Severe toxic reactions often result from the premise that gold can induce a remission, but from failure to interrupt treatment promptly when early that some patients are more resistant to treatment than

very weak upper limbs not

can

1. Landé, K. Munch. med. Wschr. 1927, 74, 1132. 2. Pick, E. Wien. klin. Wschr. 1927, 40, 1175. 3. Smith, R. T., Peak, W. P., Kron, K. M., Hermann, I. Goldman, M. J. Amer. med. Ass. 1958, 167, 1197.

F., DelToro, R. A.,

signs develop. A flexible dosage 4.

programme may

improve the results

Lawrence, J. S. Ann. rheum. Dis. 1953, 12, 129.

407

of treatment with gold; but it clearly calls for full appreciation of the principles involved, and for close supervision of patients and frequent measurements of sedimentationrate. Dermatitis and stomatitis, quickly detected, may by prompt adjustment of dosage be reduced to trivial complications; but more dangerous complications, such as thrombocytopenia, remind us that gold is a poison still to be handled with respect. CANCER AND SOIL

long speculated whether differences in cancer might not be due in some way to the soil. As

MEN have

incidence

ago as 1868, Farr and Haviland1 examined the death-rate from cancer in England and Wales in relation to the geological map and concluded that the disease was commoner in low-lying clay areas liable to seasonal flooding by rivers, while more elevated districts, especially those with underlying chalk and limestone, tended to have low death-rates. Haviland published several papers on the medical geography " of Britain, with particular reference to cancer, the last of which appeared in 1899.2 Several observations by others indicated that the nature of the soil (using the term in its widest sense) influenced cancer mortality. For the most part, these studies took the form of noting villages or small towns with a higher cancer incidence than neighbouring areas. Behla3 in Germany and Noelin France concluded that cancer incidence was increased by insufficient drainage of the subsoil. Williams5 noted that in his country practice in Anglesey cancer was much commoner in a village where the soil was " heavy " than in a neighbouring village with a sandy subsoil or a third village standing on limestone, although the inhabitants of all three were similar in diet, occupation, and habits. He deduced that " people living in clayey or retentive soils are more prone to cancer than those who dwell on porous soils such as sand or limestone ". These and other early reports have two serious weaknesses : usually it was total cancer mortality that was studied; and allowance was not made for differences in the age-structure of the populations compared. The study of regional variations in cancer incidence was put on a proper basis by Stocks,6 who investigated the age-standardised mortality in England and Wales of cancer of separate sites. Great contrasts were revealed. One of the most striking concerned the mountainous areas of Wales, which seemed to show a mortality from stomach cancer three times as great as that of the chalk areas of south-east England. Following the example set by Stocks, regional variations in cancer mortality have been studied in the Netherlands, where Tromp and Diehlfound that municipalities situated on peaty soils had a significantly higher mortality from stomach cancer than districts where sandy soils or river-clays predominated. In a study of the incidence of cancer in Anglesey, Davies and Wynne-Griffith8 found that stomach cancer tended to arise more commonly on those soils which show great biological activity because of an equable distribution of moisture at all seasons. These soils would tend to have a high content of organic matter. Legon 9 has compared the loss of weight on ignition (which, in the absence of calcareous matter, may be taken as an index of organic content) of samples of top

long

"

1. Farr, W., Haviland, A. Proc. med. Soc. Lond. 1868, Nov. 30. 2. Haviland, A. Practitioner, 1899, 62, 416. 3. Behla, R. Z. Hyg. 1899, 32, 123. 4. Noel, L. Sur la topographie et la contagion du cancer. Paris, 1897. 5. Williams, W. H. M.D. thesis, Edinburgh, 1914. 6 Stocks, P. Regional and Local Differences in Cancer Death Rates. H M. Stationery Office, 1947. 7 Tromp, S. W., Diehl, J. C. Brit. J. Cancer, 1955, 9, 349. 89 Davies, R. I., Wynne-Griffith, G. ibid. 1954, 8, 56. Legon C. D. Brit. med. J. 1952, ii, 700.

soil from areas in North Wales and the Welsh Marches. He found that this characteristic varied directly with the

mortality from gastric cancer. Investigations into the relationship

of soil to cancer of the stomach have now been carried a stage further. In the course of field research covering North Wales and parts of Cheshire, Stocks 10 arranged for soil samples to be obtained from the gardens of the last residence of persons recently deceased from cancer. The investigation covered the intestinal cancers as well as cancer of the breast and of the lung. In addition, similar soil samples were taken from the residences of persons who had died from causes other than cancer, in order to provide a control series. Some 1200 " cancer " soils and about 400 control samples were obtained. The region chosen is of particular interest because the unusually high mortality from stomach cancer in North-West Wales (already referred to) is somewhat anomalous. In England and Wales as a whole the disease has a substantially higher mortality in urban than in rural areas. Accordingly a lower-than-average mortality might be expected in North-West Wales. From the pattern of blood-groups, also, less gastric cancer than usual might be expected in this area, because here the proportion of group-A people is lower than average. Racial predisposition can be discounted, because persons of Welsh extraction living outside Wales are not unduly susceptible to the disease. The evidence therefore points to some local factor as being responsible for the excess mortality. The soil analyses reported hitherto 11 have revealed two interesting associations-though at this stage these must be regarded as tentative. Garden soils from houses where a person has died of stomach cancer after fifteen or more years’ residence have higher median concentrations of zinc and chromium than soils of similar gardens elsewhere in the same area where a person has died of a cause other than cancer or of cancer after residence of less than two years. Cobalt, iron, lead, titanium, and vanadium showed no statistical association with cancer, while nickel, the other trace element which was examined, showed a negative association. No explanation can be offered; but zinc is an essential element in the molecule of carbonic anhydrase enzyme and also possibly of the insulin molecule, and some early work suggests that zinc may be concerned with the glycolytic processes of tumour cells. But the zinc-cancer association, being evident in areas outside North Wales as well as in the high-cancer area, though it may eventually prove to be in some way related to the general level of incidence, cannot be held to account for the excess mortality in the region. The association described by Davies and WynneGriffith may, on the other hand, prove to be the local factor which accounts for the excess, because in North Wales, but not elsewhere, the organic content of soil was related to gastric cancer but not to other cancers. Three indices of organic content were used, and all gave broadly similar results. Cancer of the stomach occurs more to soils with a high organic content in relation commonly after residence of ten to nineteen years and with moderately high content after residence of twenty years or more. This work on soils is being pursued at the Department of Agricultural Chemistry of the University College of North Wales, where arrangements have been made to analyse a common garden vegetable grown on cancer and " non-cancer " soils. "

10. See Brit. med. J. July 12, 1958, p. 99. 11. Stocks, P. British Empire Cancer Campaign: annual report for supplement to part II. London, 1958.

1957;