Summary
Synopsis: Auranofin1 is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity.
Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its effect on the occurrence or progression of erosive lesions.
Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage, temporary or permanent withdrawal of auranofin may be necessary.
Auranofin is clearly a useful addition to the limited list of agents with disease- modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well- designed studies and wider clinical experience.
Pharmacodynamic Studies: Auranofin has been demonstrated to have anti-inflammatory activity as evidenced by significant (59 to 70%) inhibition of carrageenan- or kaolin-induced paw oedema in rats and UV-induced erythema in guinea-pigs. Inhibition of passive cutaneous anaphylactic reactions and adjuvant arthritis have also been demonstrated in rats.
In an in vitro model of humoral immune response, auranofin has produced inhibition of haemolytic plaque-forming cells in mouse spleen culture. Auranofin has also been shown to inhibit anti-human IgE-induced release of histamine from fragmented, passively sensitised primate lung and immunologically mediated release of slow reactive substance of anaphylaxis - both in vitro models of immediate hypersensitivity.
In vivo, auranofin 10mg gold/kg daily inhibited antibody production in sensitised rats, and decreased the ability of immune sera to participate in antibody-dependent cellular cytotoxicity and antibody-dependent complement lysis. Auranofin 2.5, 5 and 10mg gold/kg produced an increase in delayed hypersensitivity without alteration of humoral response.
Auranofin is capable of decreasing rheumatoid factor titre and restoring normal immunoglobulin concentrations in patients with rheumatoid arthritis, although the suppression is generally of a lower magnitude than that seen following sodium aurothiomalate treatment.
Numerous in vivo and in vitro tests have been performed to determine the effects of auranofin on cell-mediated immunity. In mice, auranofin was capable of stimulation of compromised oxazolone-induced contact sensitivity and delayed hypersensitivity. Most of the in vitro testing of the effects of auranofin on polymorphonuclear cell activity has been performed with cells of human origin. Human neutrophil chemotaxis was shown to be significantly impaired when cells were incubated with various concentrations of auranofin and exposed to endotoxin-activated serum. Auranofin 2.5μg gold/ml decreased (p < 0.01) human polymorphonuclear cell phagocytosis of Candida albicans. The in vitro effects of auranofin on Superoxide production as determined by chemiluminescence have been variable, with both decreases and increases in production having been demonstrated. In polymorphonuclear cells from patients treated with auranofin 6mg daily for 23 weeks, chemiluminescence was enhanced, thus casting doubt on the clinical significance of decreased Superoxide production in vitro.
Auranofin 2 and 4μg gold/ml decreased formyl-methionyl-leucyl-phenylalanine (FMLP)-induced β-glucuronidase release from human polymorphonuclear leucocytes by 35 and 62%, respectively. However, at a lower concentration (1 μg gold/ml), auranofin enhanced lysozyme release. In human polymorphonuclear leucocytes incubated with auranofin 0.5 or 1.0μg gold/ml and exposed to IgG-rheumatoid factor immune complexes, release of β-glucuronidase, acid phosphatase and lysozyme was almost completely suppressed. Polymorphonuclear cells obtained from patients with rheumatoid arthritis who responded clinically to auranofin exhibited a 43% decrease in FMLP-induced lysozyme release, while cells from non-responding patients showed no change in lysozyme release. The mechanism of inhibition of lysosomal enzyme release by auranofin is unclear, but may depend on blockade of cell membrane transport or increased intracellular concentrations of cyclic AMP.
In human mononuclear phagocytic cells, as in polymorphonuclear leucocytes, the effect of auranofin on Superoxide production or release in vitro has been variable, being suppressed by 1.5 to 2.5μg gold/ml and increased at lower concentrations. In vitro, human synovial macrophage phagocytic activity was suppressed 26% by auranofin 10 mg/ml.
In vitro, auranofin has inhibited human lymphocyte and monocyte antibody-dependent cellular cytotoxicity. Auranofin has also demonstrated possible cytostatic activity as evidenced by decreased synthesis of deoxyribonucleic acids, ribonucleic acids and protein in lymphocytes from patients treated with auranofin, and in in vitro human cell cultures of HeLa carcinoma, RAJI lymphoma, Epstein Barr virus-transformed lymphocytes and other human tumour models. Auranofin stimulated natural killer cell activity against RAJI and HAE-60 target cells, induced morphological changes in HeLa cells, and inhibited lymphocytic P388 tumour growth in mice.
In vitro, auranofin 10μg gold/ml inhibited platelet aggregation induced by ADP, adrenaline (epinephrine), or collagen. The same concentration of auranofin gold was also shown to inhibit prostaglandin E1 activity 50 to 70% in rat ovaries. Like other gold compounds, auranofin has been shown to decrease serum copper concentrations in laboratory animals and humans coincident with improvement in rheumatic symptoms.
In common with other forms of gold therapy, the exact mechanism of action of auranofin in rheumatoid arthritis is unknown. However, it most likely acts through one or more of its immunomodulating effects and/or its inhibition of lysosomal enzyme activity or release.
Pharmacokinetic Studies: On the basis of urinary and faecal recovery data, auranofin is approximately 25% absorbed following oral administration in patients with rheumatoid arthritis. The location and mechanism of auranofin absorption are unknown. Whole blood auranofin gold concentrations are haematocrit dependent, whereas concomitant plasma or serum concentrations are approximately equal. Steady-state plasma gold concentrations are dose dependent and ranged from 20 to 100 μg/ml 8 to 12 weeks following initiation of treatment with auranofin 2 to 9mg daily, respectively. No consistent correlation has been shown to exist between auranofin whole blood gold concentrations and therapeutic efficacy or toxicity.
The apparent volume of distribution of auranofin has not been reported and the intracellular distribution of the drug has not been studied. In whole blood, auranofin gold is 60% distributed to plasma, 37% distributed intracellularly, and 3% distributed to cellular membranes. In serum, 82% of auranofin gold is bound to albumin and 18% to globulin. Auranofin gold penetrates the synovial fluid of patients with rheumatoid arthritis at a concentration ratio of approximately 1 to 1.7 that of whole blood. It is not known if it is the free gold, the fraction bound to albumin, or that associated with blood cells which is pharmacologically active.
Retention of gold associated with auranofin treatment appears to be minimal. In rats, organ tissue gold concentrations are 1.4 to 3% of those observed following administration of sodium aurothiomalate. Unlike with parenteral gold compounds, skin punch biopsies in man have rarely demonstrated detectable gold concentrations following long term treatment with auranofin. However, oral and parenteral gold compounds produce minimal similar hair and nail gold concentrations following prolonged therapy.
Following 6 months of continuous treatment, the terminal serum half-life of a single dose of auranofin is about 25 days. The mean terminal total body half-life is 57 to 81 days. About 88% of a dose of auranofin is excreted in the faeces and 12% via the kidneys following long term therapy. Renal and enteric clearances have been determined to range from 0.064 to 0.261 ml/h/kg and 0.030 to 0.472 ml/h/kg, respectively.
Therapeutic Trials: Most of the clinical experience with auranofin is derived from a series of short term open and controlled studies, many of which have been designed both to assess the efficacy of the drug and to establish dosage guidelines. Unfortunately, many of the studies which have compared auranofin with other disease-modifying agents have released only preliminary findings and/or have been published in abstract form only. Therefore, definitive data regarding the long term efficacy and tolerability of auranofin compared with other disease-modifying drugs are limited.
The open studies of auranofin have generally shown it to be an effective and well-tolerated agent for the treatment of rheumatoid arthritis. In most studies auranofin (usually 6mg daily) reduced duration of morning stiffness, erythrocyte sedimentation rate, and number of tender and/or swollen joints. Side effects due to auranofin were usually mild and easily managed, only occasionally necessitating drug withdrawal.
In the dose establishment studies, auranofin 2mg daily was similar in efficacy to dosages of auranofin of 3 or 6mg daily. Higher dosages (> 6mg daily) were generally associated with more rapid improvement in laboratory and clinical manifestations of rheumatoid arthritis, but also with more frequent and/or severe lower gastrointestinal effects. Lower dosages of auranofin (< 2mg daily) often resulted in poor antirheumatic efficacy. There is substantial evidence that once-daily dosage provides efficacy equal to that of divided dosages, and is not associated with a greater incidence of toxicity.
In patients with rheumatoid arthritis, auranofin was shown to be superior to placebo in practically all assessment criteria. Comparative trials of auranofin and sodium aurothiomalate in rheumatoid arthritis have generally shown auranofin to be somewhat less effective, but also decidedly less toxic. Inefficacy was the most common cause of withdrawal among auranofin-treated patients, whereas toxicity was the main reason for discontinuation of sodium aurothiomalate. In patients with rheumatoid arthritis, the efficacy of auranofin appears to be similar to that of D-penicillamine, but somewhat less than that of aurothiopropanolsulphonate. However, auranofin generally causes fewer side effects than either agent.
Due to the methodological difficulties and differences associated with various methods of radiographic measurement of disease progression, the potential of auranofin to alter the joint narrowing and bone erosion of rheumatoid arthritis is not yet clearly defined; this is an important area for further study.
One small therapeutic trial in patients with juvenile rheumatoid arthritis has shown encouraging results with significant improvements in number and severity of swollen joints, pain on motion, tenderness of joints, and erythrocyte sedimentation rate. Double-blind controlled studies are indicated to further clarify the role of auranofin in the treatment of this disease.
Side Effects: The most frequent side effects of auranofin are gastrointestinal (about 50% of patients overall), about 30 to 40% of all patients taking auranofin experiencing loose stools or diarrhoea. Diarrhoea due to auranofin may only be transient, and will usually respond to temporary discontinuation, reduction in dose, or symptomatic treatment.
Although they occur infrequently, anaemia, leucopenia, eosinophilia and thrombocytopenia have been reported with auranofin usage. Laboratory monitoring for these problems is essential. All have been totally reversible upon discontinuation of auranofin.
Proteinuria (rarely progressing to the nephrotic syndrome) has been reported with auranofin. Mild proteinuria has sometimes reversed with simple dose reduction, although discontinuation of drug has been required in some cases. Up to 6 months may be required for complete reversal of proteinuria following discontinuation of auranofin.
Mucocutaneous reactions have also been frequent (about 30 to 40% of overall patients) in auranofin trials. Approximately 18 to 24% of all patients have experienced rash and/or pruritus. Stomatitis occurs with auranofin, but is relatively infrequent. Alopecia and conjunctivitis have also been reported, their respective incidences being 2 and 10%. Mucocutaneous reactions can readily be reversed with dose reduction or discontinuation of therapy.
Dosage and Administration: In most patients the recommended dose of auranofin is 6mg administered as a single daily dose. The effects of significant renal or hepatic dysfunction on the disposition of auranofin are not known, and its administration is not advised in patients with abnormal liver or kidney function.
Patients should be frequently monitored for gastrointestinal and mucocutaneous side effects; complete blood counts and urinalysis should be performed at at least monthly intervals. Management of gold toxicity is dependent upon the type and severity of the reaction.
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Various sections of the manuscript reviewed by: K. Bandilla, Deutsche Klinik für Diagnostik, Wiesbaden, West Germany; I.L. Bonta, Department of Pharmacology, Erasmus Universiteit Rotterdam, Rotterdam, Holland; D.E. Furst, Division of Rheumatology, University of Iowa, Iowa City, Iowa, USA; N.L. Gottlieb, Department of Medicine, School of Medicine, University of Miami, Miami, Florida, USA; I. Hafström, Department of Medicine III, Institute of Södersjukhuset, Stockholm, Sweden; F.D. Hart, Harley Street, London, England; M. Harth, Section of Rheumatology, Department of Medicine, University of Western Ontario, London, Canada; P.E. Lipsky, Department of Internal Medicine, University of Texas Health Science Center at Dallas, Dallas, Texas, USA; A. Lorber, Memorial Hospital Medical Center of Long Beach, Long Beach, California, USA; O.L. Meyers, Department of Medicine, University of Cape Town, South Africa; D. Schorn, Van der Walt Street, Pretoria, South Africa; S.H. Roth, Phoenix Arthritis Center, Phoenix, Arizona, USA; B. Wolach, Meir General Hospital, Kfar-Saba, Israel.
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Chaffman, M., Brogden, R.N., Heel, R.C. et al. Auranofin. Drugs 27, 378–424 (1984). https://doi.org/10.2165/00003495-198427050-00002
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DOI: https://doi.org/10.2165/00003495-198427050-00002