AURASOL ^®

Journal of Nutritional & Environmental Medicine (1997) 7, 295-305

CASE REPORT

Management of Rheumatoid Arthritis: Rationale for the Use of Colloidal Metallic Gold

GUY E. ABRAHAM MD FACN ¹ and PETER B. HIMMEL MD ²

¹ Optimox Corporation, 2720 Monterey St., Ste 406, Torrance, CA. 90503, USA;

² Himmel Health, Wakefield, RI, USA

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 AU I salts, during oxidation to trivalent gold (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, ten RA patients with long-standing erosive bone disease not responding to previous treatment were recruited from a private practice. Clinical and laboratory evaluations were performed prior to oral administration of 30 mg of colloidal AUo daily and thereafter weekly for 4 weeks and monthly for and additional five months. There was no clinical or laboratory evidence of toxicity in any of the patients. The effects of the colloidal gold on the 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 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 ten times lower than the pre-treatment levels being, respectively, 5.4 and 3.3 for tenderness and swelling. As a group, there was a significant improvement of functional status by 24 weeks of gold therapy: three patients were in clinical remission and one patient's status improved from totally disabled to full-time work. Evaluated individually, nine of the ten patients improved markedly after 24 weeks of colloidal gold at 30 mg/day. The cytokines interleukin-6 (IL-6) and tumor necrosis factor (TFN - ), the immune complexes IgG and IgM, and rheumatoid factor were significantly suppressed by the colloidal gold. The results of this open trial in ten 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 AU III generated by oxidation of AU I. Colloidal AUo could become an effective and safer alternative to the aurothiolates in the management of RA patients.

Keywords: rheumatoid arthritis, colloidal metallic gold.

INTRODUCTION

Aurothiolates have been used in the treatment of rheumatoid arthritis (RA) since their introduction by Forestier [1] in 1929. In a follow-up publication, Forestier [2] reported that the only forms of gold effective in the management of RA were organic compounds containing monovalent cathionic gold (AU I) covalently bound to a sulfur moiety (aurothiolates) and given by weekly intramuscular injection to achieve a total cumulative dose of 2.5-3 g. He stated that colloidal gold was ineffective, but did not mention the dosage, the form of colloidal gold, whether metallic or cathionic, nor 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], myelotoxiciy, 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 evaluated outcome variables: functional assessment and the 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 produced 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 the 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 the 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 the authors (G.E.A.) 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 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 be 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 ten 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 offers a more effective and safer alternative to aurothiolate therapy in RA patients.

MATERIALS AND METHODS

Colloidal Metallic Gold

Aqueous dispersions of colloidal gold ( Aurasol) were prepared by one of the authors (G.E.A.) at a final concentration of 1000 mg 1^-1 (1000 ppm) by the citrate method of Maclagan [16] and Frens [17], with several proprietary modifications.  The sizes of the colloid particles were less than 20 nm in several batches, confirmed by quantitative recovery after passing through a 20-nm filter.  Accelerated shelf-life studies have proved the stability of the aqueous dispersion for up to 2 years at ambient temperature.  The following metals were measured in the aqueous colloidal gold dispersion and were undetectable at 0.5 ppm (< 0.5 mg 1^-1): antimony, arsenic, barium, beryllium, cadmium, chromium, cobalt, copper, lead, mercury, molybdenum, nickel, selenium, silver, thallium, vanadium and zinc.  The lead levels were measured again in a more sensitive assay and were undetectable at 50 ppb ( < 0.05 mg 1^-1).  Sterilization was achieved by microfiltration through 100 nm pore size and sodium benzoate was used as an antimicrobial preservative.

RA  Patients

In order to minimize the placebo effect, the ten worst cases (nine of the ten seropositive) with long-standing (7-40 years' duration) erosive RA, with minimal to no response to previous treatment, were recruited from the private practice of one of the authors (P.B.H.).  Nine of the ten patients had previously received aurothiolate therapy without effect and five of the nine experienced side-effects of skin rash stomatitis and proteinuria.   The clinical data on these patients are displayed in Table 1.  Six of the ten patients were totally work disabled.  After informed consent was obtained, the patients underwent complete clinical and laboratory evaluations before the study and weekly afterwards for 4 weeks and monthly for an additional 5 months of oral colloidal gold administration.  Paired data analysis was used for statistical evaluation [18].  Clinical evaluation included performance parameters assessed by the method of Pincus et al.[19]; severity of tenderness and swelling of joints for 86 joints based on the quantitation of Lansbury [20] and the classification described in theDictionary of Rheumatic Diseases[21]; and the American Rheumatoloy Association (ARA) functional class by Steinbrocker et al.[22]: 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 a few or none of the duties of usual occupation or self-care and class IV, largely or wholly incapacitated with patient bedridden or confined to a wheelchair, permitting little or no self-care. 
Laboratory evaluation involved the following blood and urine test: hemoglobin, hematocrit, white blood cells and subsets, platelets; liver, renal functions and urinalysis.   Specialized immune function tests were performed under a contract by a commercial laboratory (Immunoscience Laboratory, Beverly Hills, USA): the cytokines tumor necrosis factor (TNF- ) and interleukins-6 (IL-6); neutral killer (NK) cells lytic activity; the immune complexes IgG, IgM and IgA; rheumatoid factor (RF) by Elisa and erythrocyte sedimentation rate (ESR).
Since the preliminary data by one of the authors (G.E.A.) suggested that amounts of up to 15 mg/day of colloidal gold were without clinical effect in RA, patients 1-5 received 30 mg/day for the first week and 30 mg/day for the first week and 60 mg/day for the second week, whereas patients 6-10 received 60 mg/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.

RESULTS

The mean body weight after 52 weeks on colloidal gold was not significantly different from the pre-treatment value, 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 (Table 2). The mean scores for tenderness and swelling were, respectively, for 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 scores were ten times lower than the pre-treatment levels being respectively 5.4 and 3.3 for tenderness and swelling , and remained low throughout the study. The duration of a.m. joint stiffness (in hours) showed a decreasing trend that reached statistical significance at 16 weeks with pre- and post-16 week mean scores of 2.8 and 0.54, respectively (p< 0.01). Self-assessed degree of fatigue showed a decreasing trend which became significant at 4 weeks and remained significantly lower with pre- and post-52 week scores for gold of 5.3 ± 1 (mean ± SE) and 2.6 ± 0.88 respectively (Table 2).

Satisfaction with ability to do activities, physician's estimate of disease activity, ARA class and functional assessment of normal activities, all improved significantly after 16 weeks of gold administration (Table 3). However, there was no change in vigorous activities and psychosocial status. Overall, when evaluated individually, nine of the ten patients improved markedly by 24 weeks of intervention, with three patients (5, 6 and 7) in clinical remission and with improved work status; the most impressive results were obtained in patient 6 who changed from totally disabled to full-time work, and ARA class IV to class I. The results of the immune function tests are displayed in Table 4. The immune complexes IgG and IgM were significantly suppressed by 16 weeks of intervention and remained low during the study period with pre- and post-52 week values (mean ± SE) for IgG and, IgM respectively, of : 34.6 ± 7.3 and 19.9 ± 3.4 (p <0.01); 24.0 ± 4.9 and 19.4 ± 2.9 (p< 0.05). IgA levels were low and did not suppress further. Both cytokines TNF-, and 241 ± 66 and 104 ± 24.5 (p < 0.05) for IL-6. RF levels were elevated prior to gold ingestion and suppressed significantly at 52 weeks with levels of 143 ± 23.7 and 117.9 ± 18.9 (p < 0.05). ESR remained elevated throughout the study period, without significant change. NK lytic activity increased significantly after 16 weeks of gold administration with pre- and post-gold mean values of 32.2 ± 2.6 and 50.3 ± 3.6 (p <0.01) (Table 4).
There was a complete absence of clinical and laboratory evidence of toxicity in the patients. Clinically, there were no reports or signs of skin rashes, stomatitis, gastrointestinal disturbances, vasomotor reactions, myalgias, arthralgias, pruritus, headache or metallic taste. There was no evidence of hematologic, renal and hepatic cytotoxicity. In fact, there were improvements of some hematologic parameters (Table 5). In six patients with an elevated platelet count over 400 before intervention, the platelets decreased to normal in all patients at 52 weeks of gold administration. The mean values were: 374 ± 26 (mean ± SE) before and 289 ± 36 after 52 weeks of gold ingestion (p < 0.01). In four patients with hemoglobin levels below 12 before gold administration, these levels increased above 12 in all patients at 52 weeks. The mean WBC levels were significantly lower at 52 weeks with pre- and post-gold levels of 9.8 + 0.85 and 7.8 + 0.71 (p < 0.05). This significant drop in the mean WBC values was due mainly to patients 2,3, 5 and 6 with pre-gold values above 10 and post-gold levels below 10. The post-gold WBC levels were within the normal range in all the patients (Table 5). Colloidal gold had a normalizing effect on these hematologic parameters.

DISCUSSION

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 the 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 the 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 generates 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 the 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 ten 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 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.  AU III causes 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 AU III [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 that the adverse immune reactions to the aurothiolates are elicited by T-cell sensitization to AU III formed in vivo through the 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 RF, the immune complexes of IgG and IgM, and the inflammatory cytokines TNF- and IL-6. The powerful anti-inflammatory properties of colloidal gold, while deboid of cytotoxicity and side-effects, could make it useful in other inflammatory and immune complex diseases.  Tissue levels of colloidal gold in the therapeutic ranges could be achieved rapidly with increased doages without the risks of the complications reported for the aurothiolates. It could become the ideal preventive measure against toxic shock syndrome by pre-surgery administration of colloidal gold.
Since colloidal metallic gold catalyzes electron transfer in oxidation-reduction reactions [36], one possible mechanism of the action of colloidal gold could be in potentiating the suppressive effect of antioxidants 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.

TABLE 1. Clinical data on the RA patients

Immune complexes	Pre-Rx	16 weeks	24 weeks	52 weeks
IgG
Mean	34.6	21.4	18.8	19.9
SE	7.3	4.4	3.0	3.4
p-value	----	<0.01	<0.01	<0.01
IgM
Mean	24.0	15.6	16.0	19.4
SE	4.9	3.1	3.5	2.9
p-value	----	<0.01	<0.01	<0.05
IgA
Mean	5.9	4.5	5.6	4.7
SE	0.81	0.79	1	0.91
p-value	----	NS	NS	NS
Cytokines   TFN -
Mean	207	105	74	----
SE	33	30	25	----
p-value	----	<0.05	<0.05	----
IL-6
Mean	241	107	104	----
SE	66	20	25	----
p-value	----	<0.05	<0.05	----
NK (lytic activity)
Mean	33.2	50.3	----	----
SE	2.6	3.6	----	----
p-value	----	<0.01	----	----
RF (Elisa)
Mean	143.6	----	145.9	117.9
SE	23.7	----	22.1	18.9
p-value	----	----	NS	<0.05
ESR (mm h-1)
Mean	42.1	32.9	35.2	36.5
SE	10.3	9.99	7.9	8.4
p-value	----	NS	NS	NS

	White blood cells ( X 1000)		Hemoglobin (g %)		Hematocrit (%)		Platelets ( X 1000)
Patient	Pre-Rx	52 weeks	Pre-Rx	52 weeks	Pre-Rx	52 weeks	Pre-Rx	52 weeks
1	6.8	6.4	14.3	14.0	42.3	42	276	305
2	11.2	9.0	14.2	14.1	41.9	42	294	390
3	10.5	7.6	13.3	13.1	41.1	40	447	275
4	7.0	5.2	11.9	13.4	35.9	40	419	332
5	10.6	7.4	13.1	12.9	39.1	38	248	211
6	15.4	8.0	10.4	13.5	32.3	41	453	359
7	11.5	12.4	11.7	13.8	36.7	43	423	359
8	10.8	10.8	14.1	13.8	42.8	41	317	226
9	6.7	5.0	11.8	12.1	35.5	36	418	381
10	7	6.6	12.5	12.3	38.3	38	446	348
	9.8	7.8	12.7	13.3	38.6	40.1	374	289
SE	0.85	0.71	0.44	0.21	1.0	0.66	26	36
p-value	----	<0.05	----	NS	----	NS	----	<0.01