Gold and gold salts - Clinical Tree

General information

Gold is a heavy yellow-colored element (symbol Au; atomic no. 79). Its symbol derives from the Latin word aurum. It is usually found as the metallic element but can occur as salts such gold telluride (sylvanite).

Auranofin is a triethylphosphine gold derivative for oral administration. Sodium aurothiomalate is water-soluble and is given intramuscularly as an aqueous solution. Aurothioglucose is water-soluble and is given intramuscularly in either an aqueous solution or an oily suspension. Sodium aurothiopropanol sulfonate, aurotioprol, and aurothiosulfate have similar actions and uses to those of sodium aurothiomalate. They are given by intramuscular injection.The clinical pharmacology of gold compounds has been reviewed [ ] as has the mechanism of action of auranofin [ , ].

Auranofin is in some respects strikingly different from the rest. Some 25% of an oral dose is absorbed through the intestinal wall and blood concentrations are some 15–25% of those reached with parenteral therapy. Auranofin is bound to cellular elements of the blood, is excreted mainly in the feces, and exhibits less tissue retention and total body gold accumulation than parenteral forms. It is more effective in acute inflammatory models and is a potent inhibitor of lysosomal enzyme release, antibody-dependent cellular toxicity, and superoxide production. Auranofin also affects humoral and cellular immune reactions. However, some have found auranofin to be rather less effective than parenteral gold. Auranofin is used in doses of 2–9 mg/day (generally 6 mg/day), which is less than the dose originally recommended.

In view of all this it is not surprising that auranofin has a distinct profile of therapeutic and adverse effects and adverse reactions, the differences being so great that one actually suspects differences in the mechanism of action between oral and parenteral forms. Like the latter, however, auranofin shows no clear correlation between whole blood gold concentrations and either efficacy or adverse reactions.

Uses

Gold compounds remain important in the treatment of rheumatic diseases. Metallic gold is still in use as a material in dental restorations and in implant materials. Gold coordination complexes have being studied as potential anticancer agents [ ], and the radioactive isotope ¹⁹⁸ Au has been used in the treatment of certain malignancies [ , ] and rheumatoid arthritis [ ]. In Japan, chrysotherapy has a reputation for efficacy in bronchial asthma [ ], but it has only a small steroid-sparing effect [ ].Auranofin has potential as an antimalarial agent [ ].

Use in rheumatoid arthritis

In rheumatoid arthritis the most commonly used gold salts are sodium aurothiomalate and aurothioglucose [ ]. There is some reason to believe that adverse reactions are less frequent with suspensions (of aurothioglucose or aurothiosulfate) than with the more rapidly absorbed solution (of sodium gold thiomalate) [ ].

Whereas gold was previously regarded as one of the most toxic drugs in the pharmacopeia, many authors share the view that adverse reactions can to an important extent be contained by individually adapted dosage regimens and careful monitoring. However, it is not strictly possible to predict the nature or timing of the complications that an individual may experience, and it has to be borne in mind that some reactions are immunological [ ]. The prevalence of adverse reactions to gold seems to be similar in patients given 25 or 50 mg of gold weekly [ ]. Some studies have suggested that the frequency of mucocutaneous and renal adverse reactions may be higher in the initial months of treatment. In one series of patients receiving gold sodium thiomalate, a plateau in the cumulative incidence of withdrawals due to rash was reached only after 40 months (45% of all patients), while withdrawals due to proteinuria reached a plateau after 18 months (l5%) [ ]. Hematological complications can occur at any stage.

It is widely considered that the patients who are most likely to develop adverse reactions to gold salts are those who react most favorably. In the past, many rheumatologists intensified treatment with high doses of gold salts until a skin eruption occurred, only then seeking to reduce to a maintenance dosage.

After withdrawal because of adverse reactions, treatment with gold compounds can be cautiously reintroduced without the previous adverse reactions necessarily reappearing. However, clearly one will not take this course if life-threatening reactions have occurred. It should always be borne in mind that many adverse reactions allegedly due to chrysotherapy may have other causes, particularly in the case of skin reactions. Most patients have been or are using other drugs at the same time. The concomitant use of penicillamine can be particularly confusing, since its pattern of adverse effects closely resembles that produced by gold.

Use in dentistry

Dental gold alloys are a source of contact hypersensitivity [ ], including contact stomatitis and skin eruptions at sites not usually associated with dentistry. Contact dermatitis to metallic gold, for example in jewelry, has also repeatedly been observed [ ]. A gold surgical clip has also caused an apparently allergic reaction, characterized by sterile abscess formation [ ]. However, such reactions are rare and may in part be due to other metals contained in the alloy.

General adverse effects and adverse reactions

Intravenous gold salts

Adverse reactions to gold salts occur in about one-third of systemically treated patients, the incidence varying from 25% to 40%. The dropout rate due to adverse reactions has been assessed as 22–26% [ ]. Children are considered to show the same pattern of adverse reactions as adults.

Cutaneous lesions are the most frequent adverse reactions to gold salts, followed by involvement of the mucous membranes and kidneys. Pruritus and a wide range of skin reactions can occur. In the gastrointestinal system inflammation can occur at all levels, from the buccal cavity to the colon. Glossitis, cheilitis, and stomatitis are less common than dermatitis. Enterocolitis is a rare but very serious complication. Mild proteinuria is often seen in patients receiving chrysotherapy, while severe nephrotic syndrome is much less common. Blood dyscrasias of any type can occur either during therapy or after withdrawal. Leukopenia and thrombocytopenia are the most common hematological complications, although both are clearly less common than the mucocutaneous and renal adverse effects. Unusual reactions include pulmonary infiltration, intrahepatic cholestasis, and peripheral neuropathy. By and large, undesirable effects are transient and mild, but occasional deaths continue to be reported, usually because of hematological complications.

Apart from the “nitritoid” cardiovascular reaction, which is unique to sodium aurothiomalate, and possible differences between slowly and rapidly absorbed gold salts in the relative frequency of adverse effects, the general pattern of adverse reactions is similar for all parenteral gold salts.

Although most adverse effects of gold have traditionally been characterized as toxic, various factors show that some of the complications due to chrysotherapy are, at least in part, manifestations of hypersensitivity. Eosinophilia, raised IgE concentrations, immune complexes, and a positive reaction to gold in the lymphocyte transformation test have been observed in association with many adverse reactions to chrysotherapy and point to immunological mechanisms [ ]. With aurothiomalate both pemphigus and erythroderma have been described [ ]. It may be that gold facilitates the development of autoimmunity in patients with rheumatoid arthritis. Gold-induced membranous glomerulonephritis is believed to be an immune complex (type III) reaction, although the role of gold in the development of proteinuria has not yet been clarified. Gold-induced antibody deficiency may be more common than is usually recognized. In 22 patients with rheumatoid arthritis subnormal serum immunoglobulin concentrations developed as a consequence of gold treatment [ ]. There were mild deficiencies of single immunoglobulin isotypes or severe deficiencies affecting two or three isotypes. There may be transient exacerbation of rheumatoid symptoms before a therapeutic response to gold occurs. In one series of 43 patients with rheumatoid arthritis serious exacerbation of the disease occurred in 17% [ ]. Tumor-inducing effects have not been observed.

Auranofin

Auranofin is well tolerated by most patients; its adverse effects resemble those of parenteral gold salts, but the pattern differs, with gastrointestinal reactions predominating. Adverse reactions to auranofin are also generally less severe. Where serious adverse reactions have been attributed to auranofin, cause and effect has usually remained in doubt. Adverse reactionsaffecting the lower gastrointestinal tract are the most common; early studies showed a change in bowel habit in some 40% of cases, but this does not often amount to frank diarrhea [ ]. The same authors noted proteinuria (4%) and hematological reactions (2%). Mucocutaneous reactions (pruritus, conjunctivitis, stomatitis) often occur but are rarely severe and are less problematic than with sodium aurothiomalate. Most adverse reactionsoccur during the first few months; age, sex, and duration of disease do not influence the risk of developing an adverse effect. The adverse reaction-related withdrawal rates for injectable gold, auranofin, and placebo were 40%, 14%, and 6% respectively. Rashes occur in some 20% of cases but rarely require withdrawal. Tumor-inducing effects have not been observed.

Aurothiomalate

Of 120 patients with rheumatoid arthritis who switched from aurothioglucose to aurothiomalate after the former was withdrawn from the Dutch market because of insufficient quality of the raw material at the end of 2001, 19 reported an adverse drug reaction with aurothiomalate that they had not previously experienced with aurothioglucose [ ]. The most common adverse effects were pruritus, dermatitis/stomatitis, and chrysiasis/hyperpigmentation. There were 29 withdrawals within 12 months because of lack of efficacy (n = 17), adverse drug reactions (n = 8), or remission (n = 3). Kaplan–Meier plots showed a survival rate with aurothiomalate of 79% after 12 months. There were no statistically significant differences in disease activity indicators during follow-up visits compared with baseline.

Metallic gold

Dental gold alloys can cause contact hypersensitivity [ ]. Contact dermatitis to metallic gold, for example in jewelry, has also repeatedly been observed [ ]. A gold surgical clip has also caused an apparently allergic reaction, characterized by sterile abscess formation [ ]. However, such reactions are rare and may in part be due to other metals contained in the alloy.

Organs and systems

Cardiovascular

Acute vasodilatory (so-called nitritoid) reactions occur in a minority of patients receiving parenteral gold, especially sodium aurothiomalate [ ]. A few minutes after injection the patient experiences weakness, flushing, hypotension, tachycardia, palpitation, sweating, and sometimes syncope [ ]. Very rarely myocardial infarction and stroke follow [ , ]. The mechanism is unknown, but it has been suggested that the vehicle might be responsible, and that aurothioglucose might therefore be preferable to sodium aurothiomalate in elderly patients or in those with a history of cardiovascular disease.

Respiratory

Gold-induced lung toxicity is an infrequent adverse effect in patients with rheumatoid arthritis and psoriatic arthritis. There are three types: interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and bronchiolitis obliterans; the first is the most frequent.

There have been two reports of gold-induced lung toxicity in psoriatic arthritis [ ].

A 54-year-old woman with psoriatic polyarthritis was treated with aurothiomalate 50 mg/week. When the cumulative dose reached 250 mg she developed weakness, dyspnea, fever, nausea, vomiting and erythematous skin lesions. Chest X-ray and CT scan showed diffuse interstitial pneumonitis. Gold was withdrawn and she was given prednisone 60 mg/day. She recovered in 6 months.
A 62-year old woman with psoriatic arthritis was given aurothiomalate 50 mg/week. After a cumulative dose of 135 mg she developed an itchy rash, dyspnea, and fever. Chest X-ray and CT scan suggested pneumonitis and she was given prednisone 40 mg/day. She recovered in 6 months.

More than 60 cases of “gold lung” have been reported and there must be many more unpublished cases. Beginning as a rule some weeks or months after starting treatment, the patient develops dyspnea on exertion, weakness, a dry cough, and malaise. Chest X-rays show bilateral pulmonary infiltrates of varying extent, but cases have been described in which the radiography is entirely normal [ ]. If chrysotherapy is continued, pulmonary insufficiency can follow. In fact two types of process need to be distinguished; fibrosing alveolitis and obliterative bronchiolitis occur and can co-exist [ ]; some patients develop proliferative and immunoallergic changes, perhaps even mimicking malignant processes. In treating rheumatism, it can be difficult to distinguish “gold lung” from rheumatoid lung disease [ ].

Bronchoalveolar lavage in “gold lung” tends to show an increase in the total cell count and predominance of the percentage of lymphocytes with an inverse helper/suppressor ratio. The prognosis is generally good; if gold is immediately withdrawn, the pulmonary lesions as a rule subside, although incomplete regression or even persistence of dyspnea and impaired lung function have been described, despite glucocorticoid therapy [ ].

The pulmonary toxicity of gold salts uncommonly causes life-threatening respiratory failure. Patients who suffer from this do not usually need mechanical ventilation, and the toxicity can be difficult to diagnose when it occurs in patients with an illness with pulmonary involvement. However, severe respiratory failure requiring mechanical ventilation has been attributed to gold salt toxicity in a patient with rheumatoid arthritis [ ]. Glucocorticoid therapy was life-saving and induced complete resolution of the lung damage.

Fatal interstitial pneumonitis has been attributed to gold.

A 65-year-old woman with seronegative rheumatoid arthritis was treated for 6 weeks with intramuscular sodium aurothiomalate 50 mg/week and prednisone 5 mg/day [ ]. Her joint symptoms improved but later she developed a rash, a dry cough, oppressive chest pain, dyspnea on exertion, weakness, and low-grade fever. An X-ray showed reduced lung volumes and a diffuse bilateral interstitial infiltrate, most marked in the lower zones. Infectious causes for the lung disorder were excluded; gold was withdrawn. She required progressively higher concentrations of oxygen to avoid hypoxemia. A chest CT scan showed a small left pleural effusion and multiple alveolar infiltrates and ground-glass opacities, which were most marked in the middle and lower zones of both lungs. Her condition deteriorated and she died of respiratory failure 18 days after admission.
A 77-year-old woman with rheumatoid arthritis was given sodium aurothiomalate 50 mg intramuscularly weekly, following a test dose of 10 mg [ ]. Her rheumatoid arthritis responded well, but after a cumulative dose of 560 mg she became progressively short of breath on exertion and generally felt unwell. She had bilateral basal inspiratory crackles and widespread ill-defined shadowing on the chest X-ray, predominantly in the middle and lower zones of both lungs. A high-resolution CT scan showed ground glass opacities, particularly in the upper zones, and thickening of the peribronchovascular interstitium and interlobular septa in the middle and lower zones. Pulmonary function tests showed a restrictive lung defect. The gold injections were discontinued and she responded well to methylprednisolone. A CT scan 10 months later showed almost complete resolution, with some heterogeneity of lung density posteriorly in the lower lobes.

Interstitial pneumonia has been described in an adult who had taken auranofin for only 6 days; glucocorticoids were required [ ].

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