Now Let Us Mark the Passing of Gold

Gold is a unique metal that is resistant to degradation by traditional chemical processes.

The development of aqua regia – a toxic mixture of concentrated nitric acid and hydrochloric acid, producing gold tetrachloride, which dissolves both gold and platinum – led to the formation of gold salts. Gold tetrachloride has a great deal of toxicity, and although it was tried in a number of diseases, it was not useful. In the 19th century, a mixture of gold and sodium chloride became the form of gold salt used. At that time, this salt was used for treating alcoholism. Later, the more tolerable salts (gold thioglucose and gold thiomalate) were developed. These agents eventually proved to be the mainstay of rheumatoid arthritis treatment from the 1960s until the 1980s.

Gold therapy (chrysotherapy) was first proposed for use in the treatment of RA by Dr. Jacques Forestier in 1930.

In 1890, Dr. Robert Koch noted that gold cyanide inhibited the growth of the tuberculosis bacillus but was not effective in the treatment of tuberculosis in humans. Further studies in 1927 and 1929 refuted the earlier work that had suggested that aurothioglucose (gold thioglucose) might be useful in the more serious forms of tuberculosis – and indeed, some of these individuals with concomitant RA found that their joint pain lessened with this therapy.

Dr. Forestier published a few small studies, and in 1935 wrote about 6 years of experience in 550 patients with RA, tuberculous arthritis, and ankylosing spondylitis suggesting efficacy in these diseases.

Prior to this, Dr. J.F. Schamberg and Dr. C.S. Wright had successfully treated a group of patients with systemic lupus erythematosus with gold injections. Later in 1949, Dr. Sollmann had successful results with gold in 50% of RA patients and in 66% of SLE patients.

The mechanism of action of gold salts in rheumatic disease is not well understood. However, it is known that these drugs have anti-inflammatory activity, inhibit inflammatory enzymes, and affect mitochondrial activity. It is now known that these drugs inhibit the expression of NF kappaB, tumor necrosis factor, and other cytokines.

Because the success of gold therapy in RA was either anecdotal or in small uncontrolled studies, the British Empire Rheumatism Council in 1961 proposed a carefully constructed prospective, double-blind, controlled study for the efficacy and toxicity of this treatment. This was the first controlled study to look at disease-modifying activity in a drug to treat RA. The data showed improvement in subjective disease activity, grip strength, number of analgesic tablets taken, inflammatory markers, and hemoglobin. They were not able to show that this treatment decreased radiologic progression. Toxic side effects were frequently seen.

With this definitive study, gold became the standard disease-modifying antirheumatic drug until the mid-1980s, when methotrexate appeared on the scene. Later, another agent – penicillamine – as added to the disease-modifying drugs mix. Patients taking either of these drugs frequently experienced side effects. With gold, these included severe skin rashes, bone marrow suppression, immune thrombocytopenia, and glomerulonephritis. As time went on, it also became apparent that at least a third of patients on gold experienced no discernible benefit, and a third stopped the drug because of lack of efficacy. When a 5-year period of treatment with gold and penicillamine was carefully studied, it was noted that the majority of patients were no longer taking therapy, usually because of efficacy, toxicity, cost, and/or inconvenience.

In addition, the lack of significant inhibition of radiographic progression led to the search for new disease-modifying agents.

During the years when gold therapy was the mainstay of definitive therapy for RA, it was administered by subcutaneous injection either at home or in the doctor's office. Frequent physician visits were required for monitoring and regular lab testing. The two agents in most common use were Myochrysine (gold sodium thiomalate), and Solganal (gold thioglucose). Both were equally effective, but it seemed that Myochrysine was less well tolerated, with an increased prevalence of skin rashes and some patients experiencing episodes of flushing and bone pain. For this reason, the better-tolerated Solganal became the intramuscular treatment of choice.

In an attempt to continue to use gold with fewer side effects and without the need for intramuscular injections, the drug Auranofin (Ridaura) became available in 1985 as an oral agent. It never really caught on because it was less efficacious – although less toxic – than injectable gold.

At the same time, methotrexate hit the market and proved to be a more efficacious and less toxic agent than was gold. Indeed, some data suggest that methotrexate slows the progression of damage to the joints in RA, which gold did not. The use of gold therapy in general gradually waned after that time.

Nonetheless, some patients who have been unable to take methotrexate and the newer biologic agents remain on gold therapy. As one speaks to practicing rheumatologists, many have one or two patient still on gold therapy. While Solganal was the preferred agent in these patients, in 1998 Schering Plough and the Food and Drug Administration entered into a dispute over the manufacturing process for this agent. In May 2002, a business decision was made by the company to discontinue the manufacture of Solganal. Myochrysine and auranofin are still on the market, but are rarely used.

Thus gold, once a very promising agent in the treatment of RA, has fallen into disuse with the approval of new agents that are both more efficacious and less toxic. There is still a very small market for this drug, however, particularly in patients who are unable to take methotrexate or cannot afford the biologic agents. Unfortunately, the choice of gold agents is now restricted by the manufacturers.

Gold has an important history in the treatment of rheumatic disease. It was the first agent to be proved to have a true disease-modifying effect and to be studied prospectively in a double-blind, controlled trial. This history holds many important lessons for us today.

Dr. Gall is professor of clinical medicine and interim director of the Arizona Arthritis Center at the University of Arizona in Tucson. He has no relevant financial interests to disclose.

Gold is a unique metal that is resistant to degradation by traditional chemical processes.

The development of aqua regia – a toxic mixture of concentrated nitric acid and hydrochloric acid, producing gold tetrachloride, which dissolves both gold and platinum – led to the formation of gold salts. Gold tetrachloride has a great deal of toxicity, and although it was tried in a number of diseases, it was not useful. In the 19th century, a mixture of gold and sodium chloride became the form of gold salt used. At that time, this salt was used for treating alcoholism. Later, the more tolerable salts (gold thioglucose and gold thiomalate) were developed. These agents eventually proved to be the mainstay of rheumatoid arthritis treatment from the 1960s until the 1980s.

Gold therapy (chrysotherapy) was first proposed for use in the treatment of RA by Dr. Jacques Forestier in 1930.

In 1890, Dr. Robert Koch noted that gold cyanide inhibited the growth of the tuberculosis bacillus but was not effective in the treatment of tuberculosis in humans. Further studies in 1927 and 1929 refuted the earlier work that had suggested that aurothioglucose (gold thioglucose) might be useful in the more serious forms of tuberculosis – and indeed, some of these individuals with concomitant RA found that their joint pain lessened with this therapy.

Dr. Forestier published a few small studies, and in 1935 wrote about 6 years of experience in 550 patients with RA, tuberculous arthritis, and ankylosing spondylitis suggesting efficacy in these diseases.

Prior to this, Dr. J.F. Schamberg and Dr. C.S. Wright had successfully treated a group of patients with systemic lupus erythematosus with gold injections. Later in 1949, Dr. Sollmann had successful results with gold in 50% of RA patients and in 66% of SLE patients.

The mechanism of action of gold salts in rheumatic disease is not well understood. However, it is known that these drugs have anti-inflammatory activity, inhibit inflammatory enzymes, and affect mitochondrial activity. It is now known that these drugs inhibit the expression of NF kappaB, tumor necrosis factor, and other cytokines.

Because the success of gold therapy in RA was either anecdotal or in small uncontrolled studies, the British Empire Rheumatism Council in 1961 proposed a carefully constructed prospective, double-blind, controlled study for the efficacy and toxicity of this treatment. This was the first controlled study to look at disease-modifying activity in a drug to treat RA. The data showed improvement in subjective disease activity, grip strength, number of analgesic tablets taken, inflammatory markers, and hemoglobin. They were not able to show that this treatment decreased radiologic progression. Toxic side effects were frequently seen.

With this definitive study, gold became the standard disease-modifying antirheumatic drug until the mid-1980s, when methotrexate appeared on the scene. Later, another agent – penicillamine – as added to the disease-modifying drugs mix. Patients taking either of these drugs frequently experienced side effects. With gold, these included severe skin rashes, bone marrow suppression, immune thrombocytopenia, and glomerulonephritis. As time went on, it also became apparent that at least a third of patients on gold experienced no discernible benefit, and a third stopped the drug because of lack of efficacy. When a 5-year period of treatment with gold and penicillamine was carefully studied, it was noted that the majority of patients were no longer taking therapy, usually because of efficacy, toxicity, cost, and/or inconvenience.

In addition, the lack of significant inhibition of radiographic progression led to the search for new disease-modifying agents.

During the years when gold therapy was the mainstay of definitive therapy for RA, it was administered by subcutaneous injection either at home or in the doctor's office. Frequent physician visits were required for monitoring and regular lab testing. The two agents in most common use were Myochrysine (gold sodium thiomalate), and Solganal (gold thioglucose). Both were equally effective, but it seemed that Myochrysine was less well tolerated, with an increased prevalence of skin rashes and some patients experiencing episodes of flushing and bone pain. For this reason, the better-tolerated Solganal became the intramuscular treatment of choice.

In an attempt to continue to use gold with fewer side effects and without the need for intramuscular injections, the drug Auranofin (Ridaura) became available in 1985 as an oral agent. It never really caught on because it was less efficacious – although less toxic – than injectable gold.

At the same time, methotrexate hit the market and proved to be a more efficacious and less toxic agent than was gold. Indeed, some data suggest that methotrexate slows the progression of damage to the joints in RA, which gold did not. The use of gold therapy in general gradually waned after that time.

Nonetheless, some patients who have been unable to take methotrexate and the newer biologic agents remain on gold therapy. As one speaks to practicing rheumatologists, many have one or two patient still on gold therapy. While Solganal was the preferred agent in these patients, in 1998 Schering Plough and the Food and Drug Administration entered into a dispute over the manufacturing process for this agent. In May 2002, a business decision was made by the company to discontinue the manufacture of Solganal. Myochrysine and auranofin are still on the market, but are rarely used.

Thus gold, once a very promising agent in the treatment of RA, has fallen into disuse with the approval of new agents that are both more efficacious and less toxic. There is still a very small market for this drug, however, particularly in patients who are unable to take methotrexate or cannot afford the biologic agents. Unfortunately, the choice of gold agents is now restricted by the manufacturers.

Gold has an important history in the treatment of rheumatic disease. It was the first agent to be proved to have a true disease-modifying effect and to be studied prospectively in a double-blind, controlled trial. This history holds many important lessons for us today.

Dr. Gall is professor of clinical medicine and interim director of the Arizona Arthritis Center at the University of Arizona in Tucson. He has no relevant financial interests to disclose.

Gold is a unique metal that is resistant to degradation by traditional chemical processes.

The development of aqua regia – a toxic mixture of concentrated nitric acid and hydrochloric acid, producing gold tetrachloride, which dissolves both gold and platinum – led to the formation of gold salts. Gold tetrachloride has a great deal of toxicity, and although it was tried in a number of diseases, it was not useful. In the 19th century, a mixture of gold and sodium chloride became the form of gold salt used. At that time, this salt was used for treating alcoholism. Later, the more tolerable salts (gold thioglucose and gold thiomalate) were developed. These agents eventually proved to be the mainstay of rheumatoid arthritis treatment from the 1960s until the 1980s.

Gold therapy (chrysotherapy) was first proposed for use in the treatment of RA by Dr. Jacques Forestier in 1930.

In 1890, Dr. Robert Koch noted that gold cyanide inhibited the growth of the tuberculosis bacillus but was not effective in the treatment of tuberculosis in humans. Further studies in 1927 and 1929 refuted the earlier work that had suggested that aurothioglucose (gold thioglucose) might be useful in the more serious forms of tuberculosis – and indeed, some of these individuals with concomitant RA found that their joint pain lessened with this therapy.

Dr. Forestier published a few small studies, and in 1935 wrote about 6 years of experience in 550 patients with RA, tuberculous arthritis, and ankylosing spondylitis suggesting efficacy in these diseases.

Prior to this, Dr. J.F. Schamberg and Dr. C.S. Wright had successfully treated a group of patients with systemic lupus erythematosus with gold injections. Later in 1949, Dr. Sollmann had successful results with gold in 50% of RA patients and in 66% of SLE patients.

The mechanism of action of gold salts in rheumatic disease is not well understood. However, it is known that these drugs have anti-inflammatory activity, inhibit inflammatory enzymes, and affect mitochondrial activity. It is now known that these drugs inhibit the expression of NF kappaB, tumor necrosis factor, and other cytokines.

Because the success of gold therapy in RA was either anecdotal or in small uncontrolled studies, the British Empire Rheumatism Council in 1961 proposed a carefully constructed prospective, double-blind, controlled study for the efficacy and toxicity of this treatment. This was the first controlled study to look at disease-modifying activity in a drug to treat RA. The data showed improvement in subjective disease activity, grip strength, number of analgesic tablets taken, inflammatory markers, and hemoglobin. They were not able to show that this treatment decreased radiologic progression. Toxic side effects were frequently seen.

With this definitive study, gold became the standard disease-modifying antirheumatic drug until the mid-1980s, when methotrexate appeared on the scene. Later, another agent – penicillamine – as added to the disease-modifying drugs mix. Patients taking either of these drugs frequently experienced side effects. With gold, these included severe skin rashes, bone marrow suppression, immune thrombocytopenia, and glomerulonephritis. As time went on, it also became apparent that at least a third of patients on gold experienced no discernible benefit, and a third stopped the drug because of lack of efficacy. When a 5-year period of treatment with gold and penicillamine was carefully studied, it was noted that the majority of patients were no longer taking therapy, usually because of efficacy, toxicity, cost, and/or inconvenience.

In addition, the lack of significant inhibition of radiographic progression led to the search for new disease-modifying agents.

During the years when gold therapy was the mainstay of definitive therapy for RA, it was administered by subcutaneous injection either at home or in the doctor's office. Frequent physician visits were required for monitoring and regular lab testing. The two agents in most common use were Myochrysine (gold sodium thiomalate), and Solganal (gold thioglucose). Both were equally effective, but it seemed that Myochrysine was less well tolerated, with an increased prevalence of skin rashes and some patients experiencing episodes of flushing and bone pain. For this reason, the better-tolerated Solganal became the intramuscular treatment of choice.

In an attempt to continue to use gold with fewer side effects and without the need for intramuscular injections, the drug Auranofin (Ridaura) became available in 1985 as an oral agent. It never really caught on because it was less efficacious – although less toxic – than injectable gold.

At the same time, methotrexate hit the market and proved to be a more efficacious and less toxic agent than was gold. Indeed, some data suggest that methotrexate slows the progression of damage to the joints in RA, which gold did not. The use of gold therapy in general gradually waned after that time.

Nonetheless, some patients who have been unable to take methotrexate and the newer biologic agents remain on gold therapy. As one speaks to practicing rheumatologists, many have one or two patient still on gold therapy. While Solganal was the preferred agent in these patients, in 1998 Schering Plough and the Food and Drug Administration entered into a dispute over the manufacturing process for this agent. In May 2002, a business decision was made by the company to discontinue the manufacture of Solganal. Myochrysine and auranofin are still on the market, but are rarely used.

Thus gold, once a very promising agent in the treatment of RA, has fallen into disuse with the approval of new agents that are both more efficacious and less toxic. There is still a very small market for this drug, however, particularly in patients who are unable to take methotrexate or cannot afford the biologic agents. Unfortunately, the choice of gold agents is now restricted by the manufacturers.

Gold has an important history in the treatment of rheumatic disease. It was the first agent to be proved to have a true disease-modifying effect and to be studied prospectively in a double-blind, controlled trial. This history holds many important lessons for us today.

Dr. Gall is professor of clinical medicine and interim director of the Arizona Arthritis Center at the University of Arizona in Tucson. He has no relevant financial interests to disclose.