Sodium Aurothiomalate
Adverse Effects
Reports show a wide range for the incidence of adverse effects of sodium aurothiomalate. However, authorities consider that with careful treatment about one-third of patients will experience adverse effects. It is also considered that about 5% of patients will experience severe adverse effects and that some of the effects will be fatal. The most common effects involve the skin and mucous membranes with pruritus (an early sign of intolerance) and stomatitis (often with a metallic taste) being the most prominent. Rashes with pruritus often occur after 2 to 6 months of intramuscular treatment and may require stopping therapy. Other reactions affecting the skin and mucous membranes include erythema, maculopapular eruptions, erythema multiforme, urticaria, eczema, seborrhoeic dermatitis, lichenoid eruptions, alopecia, exfoliative dermatitis, glossitis, pharyngitis, vaginitis, photosensitivity reactions, and irreversible pigmentation (chrysiasis).
Toxic effects on the blood include eosinophilia, thrombocytopenia, leucopenia, agranulocytosis, and aplastic anaemia.
Effects on the kidneys include mild transient proteinuria which may lead to heavy proteinuria, haematuria, and nephrosis.
Other effects reported include pulmonary fibrosis, toxic hepatitis, cholestatic jaundice, peripheral neuritis, encephalitis, psychoses, fever, and gastrointestinal disorders including enterocolitis. Gold deposits may occur in the eyes. Vasomotor or nitritoid reactions, with weakness, flushing, palpitations, and dyspnoea, may occur after injection of sodium aurothiomalate. Local irritation may also follow injection.
Sometimes there is an initial exacerbation of the arthritic condition.
Some adverse effects of gold have an immunogenic component.
Effects on the blood.
Blood disorders such as eosinophilia, leucopenia, granulocytopenia, and thrombocytopenia have occurred in patients receiving gold therapy. Eosinophilia has been reported to be the most frequent haematological abnormality. It has been estimated that thrombocytopenia develops in 1 to 3% of patients receiving gold salts.
Fatal consumption coagulopathy occurred in 4 children following the second injection of sodium aurothioglucose or sodium aurothiomalate.
Effects on the cardiovascular system.
Vasomotor or nitritoid reactions associated with gold compounds are usually transient and self-limiting and although they may be mild there have been isolated reports of associated complications such as myocardial infarction, stroke, transient ischaemic attack, and transient monocular visual loss. Most reactions have been associated with sodium aurothiomalate (a reported incidence of 4.7%) but they have also occurred with auranofin and sodium aurothioglucose. Tachyphylaxis usually occurs to the reactions and most patients are able to continue treatment but paradoxically in some the severity increases with repeated doses; 2.8% of patients receiving sodium aurothiomalate may require a change of treatment due to recurrent reactions. It is important to distinguish such reactions from true anaphylactic reactions to gold. Patients taking ACE inhibitors may be at increased risk of nitritoid reactions. Transfer of the patient to sodium aurothioglucose or reduction of the dose by 50%, injection in the recumbent position, and observation for 20 minutes have been recommended for the next few injections following a reaction.
Effects on the gastrointestinal tract.
A case report of enterocolitis due to sodium aurothiomalate has been published and 27 other cases associated with gold therapy reviewed.
Effects on the immune system.
Details of a patient who developed an immune deficiency syndrome that was attributed to gold therapy with sodium aurothiomalate.
Effects on the kidneys.
Proteinuria developed in 21 patients while receiving a standard regimen of sodium aurothiomalate. The severity of the proteinuria varied greatly and in 11 it increased for 4 months after treatment was stopped. Eight patients were considered to have developed the nephrotic syndrome. The median duration of proteinuria was 11 months, resolving in all 21 patients when treatment was withdrawn; at 24 months 3 patients were still experiencing proteinuria and it was not until 39 months that all were free of the condition. Renal biopsy indicated several types of kidney damage.
See under Auranofin for a comparative incidence of proteinuria in patients receiving sodium aurothiomalate or auranofin.
Effects on the lungs.
'Gold lung' is the term used to describe symptoms of dyspnoea on exertion, weakness, dry cough, and malaise developing some weeks or months after starting gold treatment. Pulmonary insufficiency may eventually develop. The pulmonary lesions usually subside on withdrawal of gold therapy, although persistent symptoms have been reported. Nonbacterial thrombotic endocarditis associated with gold-induced pulmonary disease has also been reported. This was considered to be a manifestation of gold-induced immune complex deposition.
Effects on the nails.
A 34-year-old woman with severe rheumatoid arthritis receiving intramuscular gold developed yellow thickened toenails and fingernails after 2 years of treatment. Although there was some improvement in nail growth on stopping treatment, some light yellow discoloration in all 20 nails persisted.
Effects on the nervous system.
Neurological complications with gold salts are infrequent but may include peripheral neuropathy, Guillain-BarrΓ© syndrome, myokymia (repeated involuntary contractions of muscle fibre), and encephalopathy. Some reports are given below.
Chrysiasis is a distinctive pigmentation that develops in light-exposed skin of patients receiving parenteral gold salts. In a study of 31 patients with chrysiasis who were receiving intramuscular sodium aurothiomalate for rheumatoid arthritis, it was noted that visible changes developed above a threshold equivalent to 20 mg/kg gold content. The severity of the pigmentation depended upon cumulative dose. Focal aggregates of gold are deposited in the reticular and papillary dermis with no obvious increase in melanin. The pigmentation is permanent but benign, although the cosmetic effects may cause some patients distress. Prevention of chrysiasis is difficult but avoidance of exposure to sunlight may be helpful.
Hypersensitivity.
Many adverse effects associated with gold treatment have an immunological basis. Patients with contact allergy to gold may exhibit a flare-up, associated with cytokine release, when given sodium aurothiomalate intramuscularly. Small amounts of nickel have been detected in sodium aurothiomalate injection and in sodium aurothioglucose injection and it has been suggested that gold therapy may also exacerbate or induce hypersensitivity to nickel.
Anaphylaxis may occur occasionally but vasomotor or 'nitritoid' reactions (see Effects on the Cardiovascular System) may produce similar symptoms.
Pancreatitis.
It was suggested that pancreatitis reported in a woman receiving gold injections and in a woman on oral gold therapy may have been due to a hypersensitivity reaction.
Treatment of Adverse Effects
The treatment of the adverse effects of gold is usually symptomatic and most effects resolve when gold therapy is withdrawn. In severe cases a chelator such as dimercaprol may be used.
Precautions
Gold therapy is contra-indicated in exfoliative dermatitis, systemic lupus erythematosus, necrotising enterocolitis, and pulmonary fibrosis. It should be used with caution in the elderly and in renal or hepatic impairment; use is contra-indicated if renal or hepatic disorders are severe. Patients with a history of haematological disorders or who have previously shown toxicity to heavy metals should not be given gold salts, nor should any severely debilitated patient.
It is recommended that diabetes mellitus and heart failure should be adequately controlled in any patient before gold is given. Patients with a history of urticaria, eczema, or colitis should be treated with caution. Patients with a poor sulfoxidation status may be more susceptible to adverse effects of sodium aurothiomalate.
Use of gold compounds with other therapy capable of inducing blood disorders should be undertaken with caution, if at all.
Because of the risk of vasomotor reactions, patients should remain recumbent for about 10 minutes after each injection.
Urine should be tested for albumin before each injection and a full blood count carried out. Patients receiving gold compounds either orally or parenterally should be warned to report the appearance of sore throat or tongue, metallic taste, pruritus, rash, buccal ulceration, easy bruising, purpura, epistaxis, bleeding gums, unexplained bleeding, menorrhagia, pyrexia, indigestion, diarrhoea, or unexplained malaise. The development of breathlessness or cough should also be reported. Effects such as eosinophilia, proteinuria, pruritus, and rash arising during gold treatment should be allowed to resolve before therapy is continued.
The manufacturer recommends that annual chest X-rays should be carried out.
Breast feeding.
The American Academy of Pediatrics considers that gold compounds are usually compatible with breast feeding.
Gold has been detected in breast milk and found bound to the red blood cells of breast-fed babies. In a report of a breast-fed infant it was calculated that the weight-adjusted dose of gold received by the infant exceeded that received by the mother although the infant exhibited no ill-effects during 100 days of breast feeding and developed normally thereafter. Nonetheless, because of the relatively high exposure it was recommended that breast-fed infants should be closely monitored.
Porphyria.
Sodium aurothiomalate has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Pregnancy.
Although there have been a number of healthy neonates born after in-utero exposure to gold compounds, animal studies and a report of malformation in a child born to a woman treated with sodium aurothiomalate led to a suggestion that gold might possibly have teratogenic effects. The manufacturer advises that sodium aurothiomalate should be avoided during pregnancy.
Interactions
There is an increased risk of toxicity when gold compounds are given with other nephrotoxic, hepatotoxic, or myelosuppressive drugs. Use of gold compounds with penicillamine may increase the risk of haematologic or renal adverse reactions.
For a discussion on the effects of previous therapy with gold salts affecting penicillamine toxicity, See auranofin . For a possible increased risk of nitritoid reactions when gold compounds are given to patients taking ACE inhibitors, see Effects on the Cardiovascular System .
Pharmacokinetics
Sodium aurothiomalate is absorbed readily after intramuscular injection and 85 to 95% becomes bound to plasma proteins. With doses of 50 mg weekly a steady-state serum concentration of gold of about 3 to 5 micrograms/mL is reached in 5 to 8 weeks. It is widely distributed to body tissues and fluids, including synovial fluid, and accumulates in the body.
The serum half-life of gold is about 5 to 6 days but this increases after successive doses and after a course of treatment, gold may be found in the urine for up to 1 year or more owing to its presence in deep body compartments. Sodium aurothiomalate is mainly excreted in the urine, with smaller amounts in the faeces.
Gold has been detected in the fetus when sodium aurothiomalate was given to the mother. Gold is distributed into breast milk.
Uses and Administration
Sodium aurothiomalate and other gold compounds are used mainly for their anti-inflammatory effect in active progressive rheumatoid arthritis and progressive juvenile idiopathic arthritis; they may also be beneficial in psoriatic arthritis. They are generally used as disease-modifying antirheumatic drugs in patients whose symptoms are unresponsive to or inadequately controlled by NSAIDs alone.
Sodium aurothiomalate therapy should only be undertaken where facilities are available to carry out the tests specified under Precautions.
Sodium aurothiomalate is given by deep intramuscular injection; the area should be gently massaged and, due to the possibility of vasomotor reactions, the patient should remain recumbent for 10 minutes and kept under close observation for 30 minutes after each injection. In the UK, 10 mg is given in the first week to test the patient's tolerance. If satisfactory, this may be followed by doses of 50 mg at weekly intervals until signs of remission occur; the dosage interval is then increased to 2 weeks until full remission occurs and then increased gradually to every 4 to 6 weeks. Treatment may be continued for up to 5 years after remission.
Improvement may not be seen until a total dose of 300 to 500 mg has been given. If no major improvement has occurred after a total of 1 g has been given (excluding the test dose) therapy should be stopped; alternatively in the absence of toxicity, 100 mg may be given weekly for a further 6 weeks; should there be no response at this dose other forms of therapy should be tried. In patients who relapse while receiving maintenance therapy, the interval between doses should be reduced to one week and should not be increased again until control has been obtained; however, if no response is obtained within 2 months, alternative treatment should be used. It is important to avoid complete relapse since a second course of gold therapy is not usually effective.
For children with progressive juvenile idiopathic arthritis the suggested initial weekly dose is 1 mg/kg to a maximum of 50 mg weekly (one-tenth to one-fifth of the calculated initial weekly dose may be given for 2 to 3 weeks to test the patient's tolerance). With full remission, the dosage interval may be increased gradually to every 4 weeks. If no improvement has occurred after 20 weeks, the dose could be raised slightly or another antirheumatic drug tried.
NSAIDs may be continued when sodium aurothiomalate therapy is begun.
Other gold compounds that have been used include auranofin, aurothioglucose, aurotioprol, gold keratinate, and sodium aurotiosulfate.
Asthma.
For comment on the use of parenteral gold compounds in the treatment of asthma, see under Auranofin.
Pemphigus and pemphigoid.
Corticosteroids are the main treatment for blistering in pemphigus and pemphigoid. Intramuscular gold therapy has been used concomitantly to permit a reduction in corticosteroid dosage although evidence for the steroid-sparing effect is lacking; it has been suggested that gold therapy should be reserved for patients who cannot tolerate corticosteroids or in whom they are contra-indicated.
Rheumatic disorders.
Gold compounds are among the disease-modifying antirheumatic drugs (DMARDs) that may be used in the treatment of rheumatoid arthritis and juvenile idiopathic arthritis . There is little agreement on which of the various DMARDs should be tried first and their selection is largely based on individual experience and preference.
Despite its toxicity intramuscular gold has long been used for the treatment of rheumatoid arthritis and is often the standard against which the efficacy of other treatments is measured. Oral gold is less toxic but is also much less effective. It is unclear if there are differences between available intramuscular forms, but a study in 120 patients converted from aurothioglucose to aurothiomalate found that 29 withdrew from the latter drug within 12 months, mostly because of lack of efficacy or the development of adverse effects not seen with the previous drug.
Gold compounds may also be of benefit in psoriatic arthritis (see under Spondyloarthropathies).