Management of Rheumatoid Arthritis: Rationale for the Use of Colloidal Metallic Gold
Management of Rheumatoid Arthritis: Rationale for the Use of Colloidal Metallic Gold
Guy E. Abraham MD FACN1 and Peter B. Himmel MD2
In Press - J. Nutr. Med., Vol. 7 - Dec. 1997
Gold salts of monovalent gold (AU I) with a gold-sulfur ligand (aurothiolates) are the only form of gold currently in use for the management of Rheumatoid Arthritis (RA). Aurothiolates have limited success and are associated with a high incidence of side effects. Metallic gold (AUo) is non-toxic and used extensively in dentistry. Monoatomic metallic gold is generated in vivo from AUI salts, during oxydation to AU III. Monoatomic gold tends to form clusters of colloid particles. It is postulated that the active ingredient in aurotherapy is AUo and the side effects are caused by AU III. To test this postulate, 10 RA patients with long standing erosive bone disease not responding to previous treatment, were recruited from a private practice. Clinical and laboratory evaluation were performed prior to oral administration of 30 mg of colloidal metallic gold daily, and thereafter weekly for 4 weeks and monthly for an additional 5 months. There was no clinical or laboratory evidence of toxicity in any of the patients.
The effects of the colloidal gold on tenderness and swelling of joints were rapid and dramatic, with a significant decrease in both parameters after the first week, which persisted during the study period. The mean scores for tenderness and swelling were respectively for the pre-and post- 1 week = 58.8 and 18.2 (p<0.01); and 42.5 and 15.9 (p<0.01).
By 24 weeks of gold administration, the mean scores were 10 times lower than pre-treatment levels being respectively 5.4 and 3.3 for tenderness and swelling. As a group, there were significant improvement of functional status after 24 weeks of gold therapy: 3 patients were in clinical remission and one patients status improved from totally disabled to full-time work. Evaluated individually, 9 of 10 patients improved markedly after 24 weeks of colloidal gold at 30 mg/day. Cytokines interleukin-6 (IL-6) and Tumor necrosis factor (TNFa) were significantly suppressed by the colloidal gold with pre- and post-24 week mean values of 270 and 104 (p<0.05) for IL-6; and 207 and 74 (p<0.05) for TNFa. The results of this open trial in 10 patients with long standing erosive RA not responding to previous treatment support the postulate that colloidal gold is indeed the active ingredient in aurothiolate therapy, and that the side effects are mainly due to the trivalent gold (AU III) generated by oxydation of AU I. Colloidal metallic gold could become an effective and safte alternative to the aurothiolates in the management of RA patients. Keywords: rheumatoid arthritis, colloidal metallic gold.
Aurothiolates have been used in the treatment of rheumatoid arthritis (RA) since their introduction by Forestier in 1929 (1). In a follow-up publication, Forestier reported that the only forms of gold effective in the management of RA were organic compounds containing monovalent cathionic gold (AU I) covently bound to a sulfur moiety (aurothiolates), and given by weekly intramuscular injection to achieve a total cummulative dose of 2.5 to 3 gm (2). He stated that colloidal gold was ineffective, but did not mention the dosage, the form of colloidal gold, whether metallic or cathionic, neither the method of administration. Several subsequent reports by various investigators have confirmed the short term efficacy of the parenteral forms of aurothiolates in RA (3), but in more recently published clinical studies with the parenteral aurothiolates, several side effects were reported: Pulmonary damage (4-7), myelotoxicity, leukopenia, thrombocytopenia, and anemia (8-12). In a recent longitudinal study of 822 RA patients receiving parenteral aurothiolate therapy over a 5 year period (13), no statistical improvement was observed in two outcome variables evaluated: functional assessment and number of painful joints. In an attempt to minimize the side effects of injectable gold complexes, an oral preparation was introduced in 1976 (14). However, this preparation caused diarrhea/loose stools in 50% of the patients, was less effective than the parenteral forms of aurothiolates and produce the same side effects as the injectable forms of gold salts although to a lesser extent.
Since chemical complexes of monovalent gold readily disproportionate in solution with formation of metallic monoatomic gold and trivalent gold according to the reaction: 3AU+® 2AUo + AU +++ (15), it would be expected that monovalent gold organocomplexes, such as the aurothiolates if administered orally or parenterally, would disproportionate in vivo with formation of metallic monoatomic gold and trivalent gold (AU III). In vivo clustering of metallic gold atoms would eventually form colloidal particles of gold. One of us (GEA) postulated that the active ingredient in aurothiolate therapy is colloidal metallic gold generated by in vivo disproportionation with subsequent clustering of monoatomic metallic gold to form colloidal gold; and that the side effects were due mainly to the trivalent gold (AU III) generated from disproportionation (Fig 1). If this postulate is valid, one would expect colloidal metallic gold to have therapeutic effects in RA and devoid of side effects. Metallic gold is non-toxic, used extensively in dentistry and is widely available in colloidal form as a nutritional supplement for human consumption. The above postulate was tested in 10 patients with long standing erosive RA with minimal to no response to previous treatment. The results obtained support the postulate that colloidal metallic gold is indeed the active ingredient in aurothiolate therapy and offer a more effective and safer alternative to aurothiolate therapy in R.A. patients.
Materials and Methods
A. Colloidal metallic gold:
B. R.A. Patients:
Performance parameters were assessed by the method of Pincus, et. al., (19). The severity of swelling and tenderness was assessed for 86 joints, based on the quantitation of Lansbury (20), and the classification described in the Dictionary of the Rheumatic Diseases (21). The American Rhematology Association (ARA) functional class by Steinbrocker, et al., (22) was used to evaluate functional status: Class I: Complete functional capacity with ability to carry on all usual duties without handicaps; Class II: Functional capacity adequate to conduct normal activities despite handicap or discomfort or limited mobility of one or more joints; Class III: Functional capacity adequate to perform only few or none of the duties of usual occupation or or self care; Class IV: Largely or wholly incapacited with patient bed ridden or confined to wheel chair, permitting little or no self care.
Since preliminary data by one of us (GEA) suggested that amounts up to 15 mg/day of colloidal gold was without clinical effect in RA, patients 1 through 5 received 30 mg/day for the first week and 60 mg/day for the second week, whereas patients 6 through 10 received 60mg/day for the first week and 30 mg/day for the second week. Except for one patient, no significant difference was found between these two amounts on the clinical parameters evaluated. The patients were therefore continued on the trial at 30 mg/day for a duration of 24 weeks.
The effects of the colloidal gold (Aurasol®) on tenderness and swelling of joints were rapid and dramatic, with a significant decrease in both parameters after the first week, which persisted during the study period. The mean scores for tenderness and swelling were respectively for the pre- and post- 1 week = 58.8 and 18.2 (p<0.01); and 42.5 and 15.9 (p<0.01). By 24 weeks of gold administration, the mean scores were 10 times lower than pre-treatment levels being respectively 5.4 and 3.3 for tenderness and swelling. Duration of AM joint stiffness (in hours) showed a decreasing trend that reached statistical significance with pre-and post 24 week mean scores of 2.8 and 0.4 respectively (p<0.01).
The mean body weight after 24 weeks on colloidal gold was not significantly different from the pre-treatment mean value. As a group, there were significant changes in ARA functional class, and physician's estimate of disease activity. Pre- and post- 24 week mean values were 2.9 and 2.3 (P<0.05) for ARA functional class; and 3.1 and 1.5 (P<0.01) for physician's estimate of disease activity. After 24 weeks on colloidal gold, 3 patients (#5, #6, #7) were in clinical remission. Work status improved in 3 patients (#3, #5, #6), with the most impressive results in patient #6, who changed from totally disabled to full time work, and ARA class IV to class I. The inflammatory cytokines IL-6 and TNFa were significantly suppressed by the colloidal gold with pre- and post-24 week mean values of 270 and 104 (p<0.05) for IL-6; and 207 and 74 (p<0.05) for TNFa.
There was no clinical or laboratory evidence of toxicity in the patients. Specifically no change was observed in subsets of white blood cells and platelets in the RA patients, supporting the absence of cytotoxicity from colloidal gold. There was no significant change in hemoglobin, hematocrit, liver function tests, BUN, serum creatinine and urinalysis in the RA patients and the levels of these parameters remained within normal limits during the study period. Clinically, there were no reports or signs of skin rashes, stomatitis, gastrointestinal disturbances, vasomotor reactions, myalgias, arthralgias, pruritus, headache or metallic taste. Evaluated individually, 9 of 10 patients improved markedly after 24 weeks of colloidal gold at 30 mg/day.
In studies performed in vitro (23) and in vivo (24), administered metallic colloidal gold particles are ultimately sequestered within lysosomes of phagocytes, visible under electron microscopy (EM). After administration of aurothiolates to RA patients, gold particles visible under EM selectively accumulate in the lysosomes of synovial cells and macrophages (25). It is believed that stabilization of lysosomes by these gold particles plays a role in their therapeutic actions (26). Electron probe x-ray analysis of lysosomes revealed that the form of gold present in lysosomes obtained from patients receiving aurothiolates is devoid of sulfur atoms and therefore cannot be in the form of aurothiolates (26). Since disproportionation of aurothiolates generate monoatomic metallic gold with a diameter of 0.28 nm, a size below the resolution of EM, the only way the gold particles in the lysosomes could be visible under EM is by clustering of metallic monoatomic gold to form colloidal gold particles. These results are consistent with the postulate that the gold in lysosomes is in the form of colloid particles of metallic gold. Therefore, the argument that colloidal metallic gold is the active ingredient from aurotherapy seems very plausible.
The results of this open trial in 10 patients with long standing erosive RA not responding to previous treatment support the postulate that colloidal gold is indeed the active ingredient in aurothiolate therapy, and that the side effects are mainly due to the trivalent gold (AU III) generated by in vivo disproportionation. Common sense would favor the active ingredient in its pure state over a precursor that generates both the active form and another form causing side effects. The most prevalent side effects of aurotherapy are skin rash and diarrhea. Trivalent gold cause contact dermatitis and skin rash (27). The diarrheogenic action of aurothiolates can be explained by their ability to stimulate intestinal secretion in vitro, an effect shared by trivalent gold (28). Aurothiolates cause adverse immune reactions in up to one third of RA patients (29-31). Some of these side effects can be reproduced in susceptible mouse strains following long-term exposure to the aurothiolates: increased serum levels of IgM, IgG and IgE formation, of IgG antinuclear antibodies, and granular IgG deposits along the glomerular basement membrane (32-34). T-lymphocytes from susceptible mice fail to be sensitized to the aurothiolates but mount a secondary response to Au (III) salts, suggesting the adverse immune reactions to the aurothiolates are elicited by T cell sensitization to Au (III) formed in vivo through oxidation of Au (I) (35).
A placebo effect in these RA patients is very unlikely since their favorable clinical response was associated with the concurrent suppression of the inflammatory cytokines TNFa and IL-6. The powerfull anti-inflammatory properties of colloidal gold while devoid of cytotoxicity and side effects could make it usefull in other inflammatory and immune complexes diseases. Tissue levels of colloidal gold in the therapeutic ranges could be achieved rapidly with increased dosages without the risks of complications reported for the aurothiolates. Colloidal metallic gold could become an effective and safe alternative to the aurothiolates in the management of R.A. patients.
Since colloidal metallic gold catalyzes electron-transfer in oxydation reduction reactions (36), one possible mechanism of action of colloidal gold could be in potentiating the suppressive effect of antioxydants on free radical formation. The mechanisms of action of colloidal gold however remain speculative at this time, and we are currently investigating such mechanisms in animal models. Acknowlegement: The authors wish to thank Ralf Albrecht for usefull discussions, and Pat Kellum for skillfull secretarial assistance.