Drugs 27: 378-424 (1984)

0012-6667/84/0500-0378/$23.50/0 © ADiS Press Limited All rights reserved

Auranofin A Preliminary Review of its Pharmacological Properties and Therapeutic Use in Rheumatoid Arthritis

M. ChajJman, R.N. Brogden, R.C. Heel, T.M. Speight and G.s. Avery ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: K. Bllndillll, Deutsche K1inik fUr Diag­nostik. Wiesbaden, West Germany; I.L. Bontll, Department of Pharmacology, Erasmus Universiteit Rotterdam, Rotterdam, Holland; D.E. Furst, Division of Rheumatology, University ofIowa, Iowa City, Iowa, USA; N.L. Gottlieb, Department of Medicine, School of Medicine. University of Miami, Miami, Florida, USA; I. Hilfttrom, Department of Medicine Ill. Institute of SOdersjukhuset, Stockholm, Sweden; F.D. Hllrt, Harley Street, London. England; M. Hllrth, 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. WOiIlCh, Meir General Hospital, Kfar-Saba, Israel.

Contents

Summary ...... ..... ........... ... .... ........ .. ... ....... ... ... ...... ..... .. ....... ...... ..... .... .... .......... ... ... .......... ... ...... .... . 379 I. Pharmacodynamic Studies ... ... .. .. .... ... .. ....... ... .. ...... .. ... ... ... .. .. .... .. ............. ... ... .. .. ...... ...... .. ..... . 383

1.1 Anti-Inflammatory Activity ...... ..... ........ .... .... ........... .. .. ... .... ... ...... ..... ... .. .. ... ...... ..... .... .... . 384 1.2 Effects on Humoral Immune Response ..... .. .... ..... .. .... ... .. ... .... .... ...... .. .. ....... ......... ... .... .. 384

1.2.1 Animal Studies ... ..... ... ..... ... ... .... ..... .. .... .. .. .... ... .. ... ... ... ........ ... ... ... .. .. ...... .. .. ... .. ... ... .. . 384 1.2.2 Human Studies ........... ... .... .... .......... .. .. ... ..... ... .. .. .... ....... ...... .... ..... ... ........ .... ... ..... .... 384

1.3 In Vitro Effects on Cell-Mediated Immunity .. .. ...... ..... ....... .. .... .. ... ... ..... ...... ... .. .... ........ 385 1.3.1 Effects on Polymorphonuclear Leucocyte Activity .. .... .. .. ........ .... .. .... ..... .. .... .. .. .. . 386 1.3.2 Effects on Mononuclear Leucocyte Activity ..... .... .. ... ............. .. ...... .. .. .. .... ....... ... .. 388

1.4 In Vitro Effects on DNA. RNA. and Protein Synthesis ..... .. .. .. .. ..... .... .... ...... ... ..... .. .. .. . 389 1.5 Other Effects ...... .... ..... .... ..... ... ... ... .... ..... ... .. .. ...... .. .. ....... .. ... ... .. .......... ..... ...... ...... ... ... .... .... 390

1.5.1 In Vitro Effect on Platelet Aggregation .......... .. ..... .. .... ... ..... ... ..... .. ....... ... .. .. .. .. .... .. 390 1.5.2 In Vitro Effect on Prostaglandin Activity .. .. ... ... ... ..... ...... ........ .. .. .. .. .... .... .... ... .... .. 390 1.5.3 Antitumour Activity In Vitro .. ..... .... ...... .... ... .. .. ...... .... ... .. .. ... .... ....... .. .. .... ... .......... . 390 1.5.4 Effects on Copper and Zinc Metabolism ......... .... .... .... .. .. ...... ... ...... .. .... ........ .. .... .. 390

1.6 Mechanism of Action ... ...... ..... .... .. ..... ..... ... .. .. .. .... .... ....... .. ... ....... ..... .. ... .... .. ....... .... ... ..... . 391 1.7 Toxicology Studies ... ... ... ... .......... ... .. .. .. ... .. ...... ... .. ..... ....... .. .. ... ...... ... ... ...... ... .. .... .... ... ... .... 392

1.7.1 Acute Toxicity .... .. ...... .. .... .. .. .. .... .... ... .. ...... ...... .. .. .. .. ..... .... .. .. .... .. ... .. ... .... ... .. .. .... .... .. 392 1. 7.2 Subacute and Chronic Toxicity ... .... ..... ....... .. .... ... ...... ... .. .. .. ... ... .. .. .. .. ..... .. .... .. .. .. .. .. 392 1.7.3 Effects on Reproduction .. .. .. .. ............... ....... ... .. .... .. ... ....... .. ..... .... ... .... .. .... ... .. .. ... .. .. 393

Auranofin: A Preliminary Review 379

Summary

2. Pharmacokinetics of Auranofin ............................................................................................. 393 2.1 Absorption ........................................................................................................................ 393 2.2 Plasma Concentrations .................................................................................................... 393 2.3 Distribution ....................................................................................................................... 395

2.3.1 Extracellular Distribution ....................................................................................... 395 2.3.2 Blood Cell Distribution .......................................................................................... 396 2.3.3 Tissue Distribution .................................................................................................. 397 2.3.4 Gold Retention ........................................................................................................ 397

2.4 Excretion ........................................................................................................................... 397 3. Therapeutic Trials ................................................................................................................... 399

3.1 Rheumatoid Arthritis ...................................................................................................... .400 3.1.1 Open Studies ........................................................................................................... .400 3.1.2 Dose Establishment Studies .................................................................................. .40 I 3.1.3 Auranofin Compared with Placebo ...................................................................... .404 3.1.4 Comparisons with Sodium Aurothiomalate ......................................................... .404 3.1.5 Comparisons with Other Agents ........................................................................... .408 3.1.6 Effects of Auranofin on the Radiographically Detected Progression of Rheumatoid Disease .................................................................................................... .409

3.2 Juvenile Rheumatoid Arthritis ...................................................................................... .412 3.3 Other Areas of Use .......................................................................................................... 412

4. Side Effects ............................................................................................................................. .412 4.1 Gastrointestinal Effects ................................................................................................... .412 4.2 Haematological Effects .................................................................................................... .413 4.3 Renal Effects .................................................................................................................... .414 4.4 Mucocutaneous Effects ................................................................................................... .414 4.5 Other Reactions ............................................................................................................... .414

5. Dosage and Administration .................................................................................................. .415 6. The Place of Auranofin in Therapy ..................................................................................... .415

Synopsis: Auranofin l 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 ejJicacy 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 ~ffect on the occurrence or progression of erosive lesions.

Aurano/in 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 e.ffect seen with auranofin. The frequency of side ({fects has heen similar with auranofin and sodium aurothiomalate. hut 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 he necessary.

Auranof/Il is clearly a useful addition to the limited list of agents with disease-modi­/i'ing potential presently availablefor the treatment of rheumatoid arthritis. It will douht·

I 'Ridaura' (Smith Kline & French).

Auranofin: A Preliminary Review 380

less 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 tOmg 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 tOmg 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 2.5/Lg gold/ml decreased (p < 0.0 I) 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 4/Lg gold/ml decreased formyl-methionyl-Ieucyl-phenylalanine (FMLP)-induced !3-glucuronidase release from human polymorphonuclear leucocytes by 35 and 62%. respectively. However, at a lower concentration (I/Lg gold/ml), auranofin enhanced lysozyme release. In human polymorphonuclear leucocytes incubated with aur­anofin 0.5 or 1.0/Lg gold/ml and exposed to IgG-rheumatoid factor immune complexes, release of !3-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 2.5/Lg gold/ml and increased at lower concentrations. In vitro, human synovial macrophage phagocytic activity was suppressed 26% by auranofin to mg/mt.

In I'itro. 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

Auranofin: A Preliminary Review 381

of HeLa carcinoma, RAJI lymphoma, Epstein Barr virus-transformed lymphocytes and other human tumour models. Auranofin stimulated natural killer cell activity against RAJ! and HAE-60 target cells, induced morphological changes in HeLa cells, and inhib­ited lymphocytic P388 tumour growth in mice.

In vitro. auranofin IOltg gold/ml inhibited platelet aggregation induced by ADP, ad­renaline (epinephrine), or collagen. The same concentration of auranofin gold was also shown to inhibit prostaglandin EI 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 Itg/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 well­tolerated 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.

Auranofin: A Preliminary Review 382

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. Double­blind 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.

Auranofin: A Preliminary Review

1. Pharmacodynamic Studies

Auranofin is an alkyl phosphine gold coordina­tion complex, containing 29% gold by weight (Bernhard, 1982a; Menninger and Burkhardt, 1983b; Sutton et aI., 1983; Walz, 1979) [fig. 1].

Auranofin is active in standard animal models of inflammation, and in inhibiting lysosomal en­zyme release from animal and human leucocytes. Both auranofin and sodium aurothiomalate inhibit cell-mediated immunity, probably due to inhibi­tion of monocyte-macrophage dependent immune reactions (Hanna et aI., 1983; Harth, 1983; Lipsky and Ziff, 1977). While both agents affect B- and T­lymphocyte function in vitro, auranofin appears to alter T-Iymphocyte activity more than that of B­lymphocytes, whereas sodium aurothiomalate seems to exert its greatest effects on B-Iymphocyte function (Lorber et aI., 1981).

CH20COCH3 GS_AU_P(C2H3h

OGaGH3 GH3GOa

Auranofin OGaCH 3

GOONa , H-C-S-Au

I H-C-H ,

GaONa

Sodium aurothiomalate

(gold sodium thiomalate)

HO-9-H--1 H-C-~H I

I 0 OH-C-~

H-r,-OH H-G , H-«-S-Au

H

Aurothioglucose

Fig. 1. Structural formulae of auranofin, sodium aurothiomalate

and aurothioglucose.

383

Interpretation of in vitro or animal data as they relate to the pharmacodynamic effects of auranofin or other gold compounds in humans should be made with considerable caution (Lorber, 1983a,b; Sliwinski and Guertin, 1982). Agents such as aur­anofin and sodium aurothiomalate exist for only brief periods in vivo as intact molecules (Furst, 1983; lellum et aI., 1979; Lewis and Walz, 1982), and this cannot be taken into account in in vitro tests. Also, culture media or drug vehicle constit­uents may react with a drug or influence its activ­ity, possibly creating artifactual effects on cellular functions (Lorber, 1983b). Finally, to conclude that in vitro effects of gold compounds have clinical sig­nificance in man, these effects should be observed with concentrations attainable in treated patients (Lipsky and Ziff, 1977). Although it is not known which fraction of total body gold is that which is pharmacologically active (see section 2.3), concen­trations of auranofin and other gold compounds utilised in in vitro tests have often far exceeded those achievable or desirable in man (Lewis and Walz, 1982) [section 2.2], and most of the inves­tigations in laboratory animals have involved greater dosages than those used to treat patients with rheumatoid arthritis (Lorber, 1983b).

Sliwinski and Guertin (1982) have presented evidence that the portion of auranofin which is ac­tive in some in vitro models of human neutrophil function may be that which is not protein bound, whereas the portion of sodium aurothiomalate which is active in the same tests is the protein­bound fraction. In contrast, more recent data from Lorber et al. (1983a) have indicated that the active portion of both drugs is that which is unbound, and that the amount of unbound serum gold correlates with the degree of suppression of lymphocyte mitogen response and phagocytosis, and respiration of circulating polymorphonuclear leucocytes from patients with rheumatoid arthritis (see section 2.3.1).

The validity of many of the in vitro compari­sons of auranofin and sodium aurothiomalate may be in doubt until the relationships between drug distribution and immunological effect are more clearly defined for both agents.

Auranofin: A Preliminary Review

1.1 Anti-Inflammatory Activity

Auranofin possesses anti-inflammatory activity as evidenced by inhibition of carrageenan- (Walz et aI., 1982a) or kaolin-induced (Lewis et aI., 1980) paw oedema in rats, inhibition of ultraviolet­induced erythema in guinea-pigs (Lewis et aI., 1980), and inhibition of passive cutaneous ana­phylactic reactions and adjuvant-induced arthritis in rats (Hertz et aI., 1983; Lewis et aI., 1980; Walz et aI., 1976).

At a dosage equivalent to 20mg of gold/kg, aur­anofin produced a greater inhibition of carra­geenan-induced paw oedema (50 to 70%) than sod­ium aurothiomalate « 40%) at dosages which produced I O-fold higher serum gold concentra­tions. The effect of auranofin is independent of adrenal function, whereas that of sodium auro­thiomalate is partially adrenal dependent (Walz et aI., I 982a).

Kaolin-induced rat paw oedema was inhibited to a greater extent by auranofin than by sodium aurothiomalate, although ultraviolet erythema in guinea-pigs was suppressed to a similar extent by both drugs (Lewis et aI., 1980). Auranofin at doses equivalent to 4, 10 and 20mg gold/kg daily pro­duced a dose-related suppression of primary and secondary lesions of adjuvant arthritis in rats, sim­ilar to that with sodium aurothiomalate 10mg gold/ kg. However, the parenteral gold compound re­sulted in a greater decrease in percentage survival (75%) at the intermediate dosage (Walz et aI., 1976).

1.2 Effects on Humoral Immune Response

1.2.1 Animal Studies In vitro, auranofin alters humoral immunity as

evidenced by the decrease in haemolysin plaque­forming cells in mouse spleen cultures plated with sheep red blood cells, and in immunologically me­diated release of slow reactive substance of ana­phylaxis from fragmented primate lung (Walz et al.. 1976).

In vivo studies in animal models have demon­strated that auranofin is capable of decreasing the ability of immune sera to participate in antibody-

384

dependent cellular cytotoxicity in rats sensitised with mouse L929 fibroblasts and in adjuvant arth­ritic rats (Walz et aI., 1979a, 1982b). Immune sera (anti-L929) from auranofin-treated rats exhibited a substantial decrease in ability to mediate antibody­dependent complement lysis.

Auranofin (lOmg gold/kg/day) suppressed 7S haemagglutinin antibody responses to sheep red blood cells in adjuvant arthritis rats (Walz et aI., 1976, I 982a), but not in sensitised mice (Walz and Griswold, 1978). Auranofin 2.5, 5 and IOmg gold/ kg stimulated delayed hypersensitivity of mice to sheep red blood cells, without altering humoral re­sponse (Walz and Griswold, 1978).

Auranofin can suppress animal humoral im­mune responses in a variety of assay systems whereas sodium aurothiomalate is most often in­active or enhances immune responses in these sys­tems (Walz et aI., 1982a,b) [table I].

1.2.2 Human Studies The therapeutic use of parenteral gold com­

pounds has been shown to be associated with de­creases in immunoglobulin concentrations and rheumatoid factor titres (Davis, 1983; Harth, 1980). Similar effects have been observed during long term auranofin therapy in patients with rheumatoid arthritis (Bergl6f et aI., 1978; Davis, 1983; Finkel­stein et aI., 1976; Lorber et aI., 1979a, 1981).

Thus, Finkelstein et al. (1976) noted a 26.5% decrease in l'-globulin concentration after 12 weeks' administration of auranofin 6 or 9mg daily to patients with rheumatoid arthritis, and Finkelstein et al. (1979) recorded decreases of 13 and 49% in mean total IgG and IgM-rheumatoid factor con­centrations, respectively, after 3 months' treatment with auranofin (mean blood gold concentration 0.55 ILg/ml). In other studies, auranofin 6mg daily for up to I year failed to alter IgG (BerglOf et aI., 1978; Hafstr6m, 1983; Lorber et aI., 1979a, 1981). Posi­tive correlations have existed between the daily dosage of auranofin and the whole blood or serum gold concentration and the magnitude of suppres­sion of abnormally high immunoglobulin concen­trations (Finkelstein et aI., 1976, 1979; Lorber et al.. 1979a). Decreases in rheumatoid factor titres

Auranofin: A Preliminary Review 385

Table I. Summary of comparative in vitro and in vivo effects of auranofin (A F) and sodium aurothiomalate (ATM) on humoral immunity

(adapted from Walz et aI., 1982a)

Reference Assay Species Effect Concentrations

AF ATM AF ATM

In vitro

Walz et al. (1979a) HPFC Mouse At 1,10 and 100 Only at 100 jlmol/L

jlmol/L

In vivo

Walz and Griswold Haemagglutinin titres Mouse 0.625-10.0mg Au/kg 0.625-10.0mg Au/kg

(1978) during delayed

hypersensitivity

Delayed hypersensitivity Mouse At 2.5, 5.0 and At 5.0mg Au/kg only

10.0mg Au/kg

Walz et al. (1976) HPFC Rat 10mg Au/kg/day 5mg Au/kg/day x 4d x 4d

7S anti-SRBC antibody Rat 10mg Au/kg/day 5mg Au/kg/day titre x 4d x 4d

Walz et al. (1979a) HPFC Mouse Initial j 20.0mg Au/kg/day 20mg Au/kg/day

later 1 x 4d x 4d

ADCC antibody Rat 10mg Au/kg/day 5mg Au/kg/day x 4d x 4d

ADCL antibody Rat 10mg Au/kg/day 5mg Au/kg/day x 4d x 4d

Walz et al. (1982b) 7S and 19S Rat j 7S titres 10mg Au/kg/day 9.3mg Au/kg/day

haemagglutination titres 119S titres x 4d x 4d

Abbreviations: HPFC = haemolytic plaque-forming cells; SRBC = sheep red blood cells; ADCC = antibody-dependent cellular cyto-toxicity; ADCL = antibody-dependent complement lysis; t = increase; j = decrease; - = no change.

and an increase in the albumin/globulin ratio ac­companied clinical improvement in 8 patients studied by Berglo[ et ai. (1978), but other studies have not demonstrated decreased rheumatoid fac­tor titres with auranofin treatment (Hafstrom, 1983; Lorber et ai., 1979a, 1981). Auranofin 6mg daily decreased concentrations of IgM and IgA signifi­cantlyafter 16,26 and 52 weeks of therapy (Lorber et ai., 1981); however, comparative studies (Kee­gan et ai., 1983; Lorber et ai. 1979a; 1981) have indicated that decreases in immunoglobulins and rheumatoid factor titre may be smaller with aur­anofin than with sodium aurothiomalate (serum or blood gold concentration ~ 3 ,",g/ml).

Dinitrochlorobenzene was administered to as­sess skin test response in patients with rheumatoid

arthritis treated with auranofin 6mg daily for an average of 45 weeks (Lorber et ai., I 979a). Skin reaction to rechallenge with dinitrochlorobenzene was prevented completely in 9 of 15 patients and partially in a further 2 patients. In contrast, thera­peutic doses of sodium aurothiomalate failed to prevent a reaction in 13 of 15 patients in a parallel group. Despite the inhibition of T-Iymphocyte function by auranofin, there was no evidence of an increased incidence of local or systemic infectious disease.

I.3 In Vitro Effects on Cell-Mediated Immunity

Auranofin and sodium aurothiomalate have

Auranofin: A Preliminary Review

been shown to affect cell-mediated immunity as determined by their influence on oxazolone-in­duced contact sensitivity and delayed hypersensi­tivity to sheep red blood cells in mice (Walz and Griswold, 1978; Walz, 1981), and experimental al­lergic encephalomyelitis in rats (Walz et ai., I 982a). Auranofin (1.25 to IOmg gold/kg) and sodium aurothiomalate (5 and 10mg gold/kg) were capable of stimulating compromised oxazolone-induced contact sensitivity, but neither agent significantly altered the uncompromised response in normal mice and only auranofin (5mg gold/kg) stimulated immune response in mice which had been im­munosuppressed with methotrexate. In stimula­tion of delayed hypersensitivity to sheep red blood cells (also see table I), similar activity occurred at concentrations of auranofin which were one-half those of sodium aurothiomalate. In rats, auranofin and sodium aurothiomalate inhibited the onset (but not the cumulative incidence) of experimental al­lergic encephalomyelitis (Walz et ai., 1982a).

Antibody-dependent cellular cytotoxicity me­diated by rat peripheral blood polymorphonuclear leucocytes was markedly decreased (~ 94%) by aur­anofin 2JLg gold/ml, whereas the process was shown to be enhanced in the presence of auranofin 0.2JLg gold/ml or less (Di Martino and Walz, 1980). The cells had been pretreated with auranofin and then washed prior to testing, indicating that this was a direct inhibitory effect on the polymorphonuclear cells, and not on the antibody or target cell com­ponents of the reaction.

The in vitro effects of auranofin on lymphocyte antibody-dependent cellular cytotoxicity appear to be concentration dependent, and perhaps also dependent on the method of cell exposure to the drug. In vitro, human lymphocyte antibody-de­pendent cellular cytotoxicity was affected only slightly by auranofin 0.25 to 1.0JLg gold/ml, but markedly to almost completely inhibited by higher concentrations of 1 to 2.5JLg gold/ml (Finkelstein et ai., 1982b; Russell et ai., 1982). In vivo, de­pressed baseline lymphocyte antibody-dependent cellular cytotoxicity in patients with rheumatoid arthritis was corrected by administration of aur­anofin 6mg daily (producing serum gold concen-

386

trations of approximately 0.5 JLg/ml) [Finkelstein et ai., 1982b]. Although further data are required to confirm these findings, auranofin appears to re­store depressed antibody-dependent cellular cyto­toxicity in vivo, and inhibit it in in vitro settings.

In low concentrations (0.25 to 0.50JLg gold/ml), auranofin has been shown to cause marked in vitro stimulation of human natural killer cell activity against RAJ!, K-562 and HAE-60 target cells. However, natural killer cell activity against these targets was decreased by higher auranofin concen­trations (~ 1.0JLg gold/ml) [Harris et ai., 1983; Rus­sell et ai., 1982]. In mostly higher concentrations (0.1 to 1O.0JLg gold/ml), auranofin suppressed both T- and B-Iymphocyte proliferative responses in vitro via stimulation of suppressor cell activity (Koba­yashi et ai., 1982).

In phytohaemagglutinin-stimulated human lymphocytes, auranofin 1JLg gold/ml inhibited the incorporation of 3H-thymidine into DNA by 98% and 16% when present for 72 and 2 hours, respec­tively (Finkelstein et ai., I 977a). Protein synthesis was also significantly (88%) blunted following 72 hours of incubation with auranofin. Since the in­hibition induced by auranofin could not be re­versed by cell washing, it may have been due to interference with 'normal' lymphocyte membrane transport activity, as evidenced by inhibition of membrane transport of 3H-thymidine. However, similar studies did not show decreased membrane transport of 3H-2-deoxy-D-glucose (Simon et ai., 1979a,b) [section 1.4]. Phytohaemagglutinin mi­togen stimulation was not inhibited by sodium au­rothiosulphate IJLg gold/mi.

Lymphocytes from patients with rheumatoid arthritis who were treated with auranofin 3mg twice or thrice daily for 20 weeks produced an 80% suppression of phytohaemagglutinin-stimulated in­corporation of 3H-thymidine into DNA (Lorber, 1983a; Lorber et ai., 1981).

1.3.1 Effects on Polymorphonuclear Leucocyte Activity In polymorphonuclear cells isolated from

healthy volunteers or patients with rheumatoid arthritis, neutrophil chemotaxis in response to

Auranofin: A Preliminary Review

endotoxin-activated serum was significantly im­paired by auranofin at concentrations as low as I to 4 Ilg/ml (Hafstrom et aI., 1983b; Schienberg et aI., 1979) but neutrophil random migration was not affected (Hafstrom et aI., 1983b). In vitro neutro­phil chemotaxis in response to endotoxin-activated serum was stimulated in another study by a similar concentration range of auranofin (approximately 0.7 to 7.0 Ilg/ml) [Marcolongo et aI., 1983]. Stimu­lation of polymorphonuclear cell migration was demonstrated in cells from patients with rheuma­toid arthritis treated with auranofin 6mg daily for 23 weeks (Hafstrom et aI., 1983a).

Phagocytosis of Candida albicans by human polymorphonuclear cells was shown to be de­creased (p < 0.01) by auranofin 0.5 to 2.51lg gold/ ml (Davis et aI., 1 982b).

The oxidative metabolites produced during ac­tivation of polymorphonuclear cells by particulate or soluble stimuli are collectively termed the 'res­piratory burst', and can be measured by use of a chemiluminescence assay. Auranofin 0.5 to 2.5 Ilgj ml gold significantly decreased chemiluminescence in human polymorphonuclear leucocytes stimu­lated by zymosan (Davis et aI., 1982b) and de­creased superoxide production during immune

387

complex and 'frustrated' phagocytosis (where im­mune complexes were fixed to micropore filters) [Roisman et aI., 1982]. Chemiluminescence in­duced by either particulate or soluble stimuli was increased after human polymorphonuclear cell in­cubation with auranofin 1 to 2 Ilgjml, but de­creased following incubation with auranofin 4 Ilgj ml (Hafstrom et aI., 1982). Similarly, auranofin 6mg daily for 23 weeks stimulated chemiluminescence in polymorphonuclear cells of patients with rheu­matoid arthritis rather than inhibiting the process (Hafstrom et aI., 1983a,b). The variability ofthese findings may cast some doubt on their clinical sig­nificance. If auranofin actually decreases the pro­duction of superoxide radicals, the inhibition is probably a result of a direct action of the drug rather than a suppression of phagocytosis, as evidenced by its inhibition of chemiluminescence and super­oxide production by soluble stimuli (Davis et aI., 1983; Hafstrom et aI., I 983b). There is some in vitro evidence to indicate that auranofin inhibits superoxide production in human polymorphonuc­lear cells by modulation of ligand-receptor cou­pling and nicotinamide-adenine dinucleotide phos­phate oxidase activity (Minta et aI., 1983).

Auranofin has significantly decreased lysosomal

Table II. Summary of comparative studies of the in vitro effects of auranofin (AF) and sodium aurothiomalate (ATM) on poly­morphonuclear leucocyte activity (adapted from Walz et aI., 1982a)

Reference Function Effect Gold concentrations (pg/ml)

AF ATM AF ATM

In rat polymorphonuclear cells

Di Martino and Walz (1977) Lysosomal enzyme release .... b 0.2-20.0 20b

Di Martino and Walz (1980) ADCC ~. 2.0· 2.0

In human polymorphonuclear cells

Davis et al. (1982b) Superoxide production 0.5-2.5 1.0-100.0

PhagocytOSiS 0.5-2.5 1.0-100.0

Roisman et al. (1982) Superoxide production l (47-72%) l (15%) 1.0 40.0

Wolach et al. (1981) Aggregation l (20-100%) ~ (35%) 1.0-4.0 40.0

Lysosomal enzyme release ~ ~ 2.0 200.0

a t at 0.2"g Au/mi. b ) at 0.2"g Au/ml. Abbreviations: ADCC = antibody-dependent cellular cytotoxicity; t = increase; l = decrease; .... = no change.

Auranofin: A Preliminary Review

enzyme release to soluble and particulate stimuli in most in vitro laboratory assessments (table II), although one group (Hafstrom et aI., 1983a) has noted a 'biphasic' effect on enzyme release. Aur­anofin 2ILg gold/ml reduced formyl-methionyl-leu­cyl-phenylalanine (FMLP)-induced lysozyme and {1-glucuronidase release by 35 and 62%, respec­tively, in human polymorphonuclear leucocytes (Wolach et aI., 1981). A greater concentration of 4ILg gold/ml reduced FMLP-induced secretion of lysozyme, {1-g1ucuronidase, myeloperoxidase and lactoferrin 61.5,61.7,84.8, and 50.0%, respectively (Wolach et aI., 1982). Auranofin 4ILg gold/ml de­creased FMLP-stimulated lysozyme release by 26%, but a concentration of IlLg gold/ml increased re­lease by 51 % (Hafstrom et aI., 1982, 1983b). A sim­ilar biphasic response in {1-g1ucuronidase release also occurred when neutrophils were stimulated with FMLP. In the polymorphonuclear cells from patients with rheumatoid arthritis who had dem­onstrated a clinical response to auranofin, FMLP­induced lysozyme release was decreased 43%. Patients who had shown no response to the drug had no change in lysozyme release from baseline values (Hafstrom et aI., 1982, 1983a,b). When hu­man polymorphonuclear leucocytes were exposed in vitro to IgG-rheumatoid factor immune com­plexes following incubation with auranofin 0.5 to 1.01Lg gold/ml, the concentrations of {1-g1ucuroni­dase, acid phosphatase and lysozyme released dur­ing immune complex phagocytosis were decreased 100, 80, and 30 to 100%, respectively (Finkelstein et aI., I 977b, I 982a).

The mechanism by which auranofin acts to de­crease lysosomal enzyme release is unclear. As aur­anofin has been shown to inhibit cellular mem­brane transport mechanisms by its inhibition of 3H_ thymidine transport through lymphocyte cell membrane (Finkelstein et aI., 1977a), it may act at a cellular level to block lysosomal enzyme release (Finkelstein et aI., 1982a). Additionally, auranofin has been shown to be associated with increases in intracellular cyclic AMP concentrations (Schein­berg et aI., 1981) which are in tum known to cause decreased lysosomal enzyme release from poly­morphonuclear cells (Zurier et aI., 1974). Sodium

388

aurothiomalate and aurothioglucose do not inhibit lysosomal enzyme release, but inhibit enzyme ac­tivity (Vernon-Roberts, 1979).

Auranofin 1 to 4ILg gold/ml was shown to in­hibit FMLP-induced aggregation of cytochalasin B­treated human polymorphonuclear cells from 20 to 100% (Wolach et aI., 1981, 1982), but did not in­hibit polymorphonuclear cell aggregation in rabbits infused with zymosan-activated serum following the administration of auranofin 10 or 20 mg/kg/ day for 3 days, thus shedding doubt on the sig­nificance of the in vitro findings (Wolach et aI., 1982). In vitro adherence and aggregation (FMLP­induced) of human polymorphonuclear cells were enhanced by auranofin 1 to 4 ILg/ml, but aggrega­tion induced by leukotriene B4 was not influenced (Hafstrom et aI., 1983a).

1.3.2 Effects on Mononuclear Leucocyte Activity The relative effects of auranofin and sodium

aurothiomalate on mononuclear leucocyte activity are summarised in table III.

In rat mononuclear leucocytes, pretreatment with auranofin 2ILg gold/ml resulted in significant (p ~ 0.05) enhancement of mononuclear cell and target cell contact in the presence or absence of im­mune sera (Di Martino and Walz, 1980). In human mononuclear phagocytic cells isolated from peri­pheral blood of healthy volunteers and patients with rheumatoid arthritis, auranofin 1.5 to 2.51Lg gold/ ml produced inhibition of FMLP-induced super­oxide radical release (Davis et aI., 1982a). This in­hibition was most notable in cells derived from patients with rheumatoid arthritis. In some cases, a stimulatory effect on the 'respiratory burst' (see section 1.3.1) was observed in these mononuclear cells when exposed to lower concentrations of aur­anofin (0.25 to 1.01Lg gold/ml) [Davis et aI., 1982a].

In a placebo-controlled trial (Coughlan et aI., 1983) IgG and IgM-rheumatoid factor production were decreased 85 and 81 %, respectively, in mon­ocytes from patients with rheumatoid arthritis treated with auranofin 3mg twice daily for 4 months. An 84% depression of lymphocyte con­canavalin A transformation was also noted; how-

Auranofin: A Preliminary Review 389

Table III. Comparative effects of auranofin (AF) and sodium aurothiomalate (ATM) on human mononuclear leucocyte function in vitro

(adapted from Walz et aI., 1982a)

Reference Function Effect

AF

Davis et al. (1982a) Mononuclear phagocyte superoxide production

Finkelstein et al. (1982b) Lymphocyte ADCC

Harris et al. (1983) Natural killer cell activity

Lorber et al. (1981) Lymphocyte mitogen stimulation + (80%)

Russell et al. (1982) Monocyte ADCC

Lymphocyte ADCC _c

Salmeron and Lymphocyte nitrogen stimulation + (99% +) Lipsky (1983)

Scheinberg et al. (1981) Monocyte chemotaxis + (92%)

a Inhibition occurs only in absence of macrophages. b Inhibition occurs in presence or absence of macrophages.

ATM

+ (30%)

+ (up to 26%)

+ (46%)

Gold concentrations ("g/ml)

AF ATM

1.5-2.5 1-100 0.25-1.0

1.0-2.0 2-20.0

0.25-0.50 10

> 2.58 > 10b

_c _c

1.5 Not specified

0.25-1.0 Not specified 2.5

1.45-14.5 2.5-25

10"g Aud 10"g Aud

c Mononuclear cells tested in vitro following removal from patients after AF 6mg daily for 20 weeks (mean serum gold concentration

0.3-1.0 "g/ml) or ATM 50 or 75mg weekly x 20 weeks (mean serum gold concentration> 3 "g/ml, 7 days post-administration).

d Concentration of AF or ATM gold/Boyden chamber.

Abbreviations: ADCC = antibody-dependent cellular cytotoxicity; + = decrease; t = increase; - = no change.

ever, IgM production and monocyte phagocytosis of Candida albicans were not significantly affected by the treatment.

In monocytes derived from healthy volunteers and patients with rheumatoid arthritis, concentra­tions of auranofin ranging from 0.1 to I O.O~g gold/ ml markedly reduced chemotactic activity, with I O.O~g gold/ml causing a 92% reduction in peri­pheral blood monocyte chemotaxis (Kleine, 1983; Scheinberg et aI., 1981). Significant in vitro inhi­bition of human monocyte chemotaxis by auran­ofin was also demonstrated by Kleine et ai. (1981) and Scheinberg et ai. (1979). Auranofin 0.12S~g gold/ml reduced by up to SO% the capacity of hu­man monocytes to undergo antibody-dependent cellular cytotoxicity in response to antibody-coated red blood cells (Kleine, 1983; Russell et aI., 1982).

Synovial macrophage phagocytic activity in synovia removed from patients with rheumatoid arthritis was suppressed 26% by auranofin 10 mg/

ml and aurothioglucose 3 mgfml (Jessop et aI., 1982).

1.4 In Vitro Effects on DNA, RNA, and Protein Synthesis

In vitro, auranofin 0.5 to 1.0~g gold/ml selec­tively decreased DNA, RNA, and protein synthesis in human cell cultures of HeLa (epitheliod) carci­noma, RAJI lymphoma, and Epstein-Barr virus­transformed human lymphocytes. Within the ini­tial 2 hours of incubation with auranofin, DNA synthesis was inhibited by 73 to 83% in Epstein­Barr virus-transformed cells and by 90% in RAJI cells in contact with I~g gold/ml. Significant in­hibition of RNA and protein synthesis occurred at 24 hours in Epstein-Barr virus-transformed cells and at 2 hours in RAJI cells, but did not persist (Simon et aI., 1979a,b). In HeLa cells, however, auranofin O.S and 1.0~g gold/ml persistently inhib-

Auranofin: A Preliminary Review

ited incorporation of 3H-thymidine into DNA by 70 and 90%, respectively. As in other cell prepar­ations, the effect on RNA and protein synthesis was less marked than that on synthesis of DNA. Membrane transport of 3H-2-deoxy-D-glucose was not blocked by auranofin, suggesting that de­creased membrane transport was not a primary mechanism of action in the inhibition of DNA syn­thesis (Simon et aI., 1979a, b).

Significant morphological changes (rounding, pitting, tearing, and 'blebbing' of the cell mem­brane) occurred in HeLa cells following incubation with auranofin 0.5 to 1.0JLg gold/ml for 6 hours (Simon et aI., I 979a,b). The cause of these changes is unclear. However, auranofin induces a dose-re­lated decline in oxygen uptake and viability in HeLa cells, which parallel these morphological changes. The changes are suggestive of cell cycle sensitivity to auranofin or membrane damage and cell death (Lorber, 1982). Similar morphological changes oc­cur in peripheral lymphocytes of patients with rheumatoid arthritis treated with auranofin, but not in untreated patients or patients administered sod­ium aurothiomalate (Lorber et aI., 1 979a).

Structural analogues of auranofin (with methyl, isopropyl, or phenyl group exchanges in the tri­ethyl phosphine moiety of the molecule) in concen­trations of 0.25 to 1.0JLg gold/ml have also been shown to decrease 3H-thymidine incorporation into the DNA of HeLa cells, while inducing morpho­logical changes identical to those caused by the parent compound (Simon et aI., 1983).

1.5 Other Effects

1.5.1 In Vitro Effect on Platelet Aggregation In platelet-rich plasma derived from human

blood, auranofin 10JLg gold/ml was found to be a potent inhibitor of platelet aggregation induced by ADP, adrenaline, or collagen (Nathan et aI., 1982). Inhibition was most evident during the second phase of aggregation, and was directly proportional to drug preincubation time. In parallel studies, aurothioglucose caused less inhibition of collagen­and adrenaline-induced platelet aggregation. The mechanism by which auranofin decreases aggre-

390

gation of platelets is not known; however, the abil­ity of auranofin to increase platelet cyclic AMP concentrations (similar to those seen in leucocytes following auranofin) [Scheinberg et aI., 1981], or to inhibit prostaglandin function (Lamprecht et aI., 1981) [section 1.5.2], may contribute to this effect.

1.5.2 In Vitro Effect on Prostaglandin Activity Auranofin IOJLg gold/ml suppressed the stimu­

latory action of prostaglandin E, on ovarian cyclic AMP formation by 50 to 70% in prepubertal rat ovaries (Lamprecht et aI., 1981). This inhibitory effect was blocked by dithiothreitol, indicating that auranofin exerted its action through interference with protein sulfhydryl groups. Although it is known that gold compounds may interfere (how­ever weakly) with prostaglandin biosynthesis, these results appear to indicate that auranofin is capable of blocking plasma membrane prostaglandin re­ceptor-mediator events.

1.5.3 Antitumour Activity In Vitro Due to the impressive inhibitory effects of aur­

anofin on essential cellular functions (DNA, RNA, and protein synthesis, respiration, etc.) in cultured human cancer cells (HeLa, KB, RAJI) and patient mitogen and skin test responses (sections 1.2.2, 1.3 and 1.4), the antitumour activity of auranofin in mice inoculated with lymphocytic leukaemia P388 was studied (Simon et aI., 1981). Auranofin 3 to 7.5 mg/kg inhibited the growth of this tumour in mice. and in some cases was more active than 5-fluorouracil. Treatment of leukaemic mice with auranofin was also associated with significant pro­longation of the median survival time. Since aur­anofin was active in this tumour model and in in vitro propagated human cancers [B16 melanoma; HT-1080 human sarcoma; HT-29 human colon carcinoma; chago, human bronchogenic adenocar­cinoma (Crooke and Mirabelli, 1983; Mirabelli and Crooke. 1983)1 and is well tolerated, further in­vestigational studies of its anti tumour efficacy may be indicated.

1.5.4 Effects on Copper and Zinc Metabolism Gold compounds have been shown to exert ef-

Auranofin: A Preliminary Review

fects on copper (Lewis et aI., 1980; Mason et aI., 1980) and zinc (Mason et aI., 1980; Ward et aI., 1981) homeostasis. Auranofin decreased plasma copper concentrations in adjuvant arthritic rats coincident with reducing inflammation (Lewis et aI., 1980), and a positive correlation (p < 0.01) was found between reduction in erythrocyte sedimen­tation rate and decrease in plasma copper concen­trations in patients with rheumatoid arthritis re­sponding to auranofin or sodium aurothiomalate (Ward et aI., 1981, 1983a). Among the 12 patients who responded to auranofin or sodium aurothio­malate and had low initial plasma zinc concentra­tions « 10.0 J.Lmol/L), 10 demonstrated increases in zinc concentrations which existed in significant inverse correlation with the decreases in plasma copper concentrations. Although the significance of these data is not known, they suggest that an interrelationship between copper and zinc plasma concentrations exists in patients with rheumatoid arthritis responding to auranofin and other gold compounds.

1.6 Mechanism of Action

There is a wealth of evidence which strongly suggests that immunological processes playa ma­jor role in the chronic synovitis which is charac­teristic of rheumatoid arthritis (Gilliland and Man­nick, 1980; Lipsky and Ziff, 1977; Salmeron and Lipsky, 1982). It would seem reasonable to suggest that the effectiveness of auranofin may be due to its ability to modify various immunological pro­cesses. Most in vitro and in vivo studies have dem­onstrated the immunosuppressant properties of auranofin, but a few have reported immunological enhancement (sections 1.2 through 1.3.2; tables I, 11 and III). The effects of aura no fin on the immune system may be condition-dependent, with immunostimulation or inhibition depending upon prevailing conditions. Thus, auranofin has been termed an 'immunoregulating' or an 'immunom­odulating' agent (Bernhard, 1982a; Kaplan, 1983; Lewis et aI., 1980; Lorber et aI., 1981, 1982; Walz et aI., 1981). However, despite such findings, whether the effects of auranofin on immune func-

391

tion hold any significance for the patient with rheumatoid arthritis remains somewhat specula­tive, and will likely only be clearly understood when the aetiology of rheumatoid arthritis is known.

The formation of immune complexes and rheu­matoid factors are thought to be a stimulus to joint destruction in rheumatoid arthritis (Bonta et aI., 1980), and some of the activity of auranofin on immune system function may be related to its in­hibitory effects on protein formation (sections 1.3 and 1.4). In patients with rheumatoid arthritis re­sponding to gold treatment, increases in albumin concentrations are often accompanied by decreases in serum immunoglobulin concentrations, suggest­ing that gold compounds do not act by a general suppression of protein synthesis (Harth, 1979). It is unclear, however, whether auranofin decreases antibody and serum immunoglobulin concentra­tions by a direct and selective interference with protein synthesis, or indirectly via an effect on the triggering aetiological factor(s) of the disease (Fin­kelstein et aI., 1976; Harth, 1979). Inhibition of synovial cell proliferation and collagen synthesis may also contribute to the beneficial effects of gold compounds in rheumatoid arthritis (Bonta et aI., 1980).

Inhibition of lysosomal enzyme synthesis or ac­tivity may be responsible for some of the activity of gold compounds in rheumatoid arthritis (Bonta et aI., 1980; Oi Martino and Walz, 1977; Finkel­stein et aI., 1982a; Lewis et aI., 1980; Menninger and Burkhardt, 1983a). Lysosomes are the princi­pal site of gold localisation and concentration in tissues (Shaw, 1980). The lysosomal bodies con­taining soluble gold compounds have a particular morphological pattern, and have been termed 'au­rosomes' (Ghadially, 1979). Neutrophils and phag­ocytic synovial cells are known to secrete lyso­somal enzymes into joint spaces during immune complex phagocytosis and following phagocytic cell contact with antigen-antibody complexes, resulting in inflammation and tissue injury (Finkelstein et al.. I 982a). In cells removed from laboratory ani­mals and man, auranofin has been shown to be a potent inhibitor of i3-glucuronidase, lysozyme, and acid phosphatase release, and of cathepsin-B, ac-

Auranofin: A Preliminary Review

tivity (Bonta et al., 1980; Di Martino and Walz, 1977; Di Martino et al., 1974; Finkelstein et al., 1982a; Ladizesky et al., 1979) [section 1.3.1]. Since the synovial fluid from patients with rheumatoid arthritis has been shown to be rich in these en­zymes, any direct or indirect pharmacological in­terference with these substances may be of value in modulating the inflammatory response and in­hibiting the destruction of cartilage and bone (Bonta et al., 1980; Finkelstein et al., 1982a).

Gold compounds are known to inhibit prosta­glandin synthesis, and this has been suggested as a possible mechanism of action in rheumatoid arth­ritis (Bonta et al., 1980; Gottlieb, 1977; Hanna et al., 1983; Lamprecht et al., 1981; Lewis et al., 1980). The inhibition induced by gold compounds is weak (Bonta et aI., 1980); however, auranofin has been demonstrated to inhibit prostaglandin activity, and not synthesis (Lamprecht et aI., 1981) [section \.5.2]. Although blockade of prostaglandin activity occurs in vitro, it is not known whether it occurs to any significant degree in patients with rheu­matoid arthritis treated with auranofin.

Other proposed mechanisms of action for aur­anofin and other gold compounds have been in­activation of the first component of complement (Gottlieb, 1977; Harth, 1979; O'Duffy, 1979), an anti-infective action (Bonta et aI., 1980; O'Duffy, 1979), and a lowering of serum copper concentra­tions (Lewis and Walz, 1982; Lewis et aI., 1980; Mason et aI., 1980; Ward et aI., 1981, 1983a). However, as there is no convincing evidence that a bacterium or virus is the initiating agent in the immunological and inflammatory processes which constitute rheumatoid arthritis, the suggestion of an anti-infective mechanism for gold compounds is one which is highly conjectural (Gilliland and Mannick, 1980). Auranofin has been shown to de­crease serum copper concentrations in adjuvant arthritic rats and in patients with rheumatoid arth­ritis coincident with disease improvement (section 1.5.4). and it has been suggested that displacement of this trace element from abnormal binding sites may favourably modify the course of rheumatoid arthritis (Lewis et aI., 1980; Ward et aI., 1983a). However. different gold compounds exert varying

392

effects on copper homeostasis (Mason et aI., 1980), despite having similar efficacy in rheumatic dis­eases. It is not yet clear whether an elevated or a decreased (from baseline values) serum copper concentration is most consistent with optimal anti­rheumatic activity (Lewis et aI., 1980).

1.7 Toxicology Studies

1.7.1 Acute Toxicity The acute toxicity of auranofin has been eval­

uated in Charworth Farm Swiss mice and in Charles River rats, in which the median lethal oral doses were 310 and 265 mg/kg, respectively (Saunders, 1983).

1.7.2 Subacute and Chronic Toxicity In a I-year study, auranofin 1.0, 3.5, and 1O.Omg

gold/kg daily produced dose-related changes in rats, including weight loss, increased salivation, soft faeces, anaemia and leucocytosis (Payne and Ar­ena, 1978a). The haematological abnormalities were believed to be secondary to auranofin-induced gas­trointestinal lesions, rather than direct effects on the bone marrow. Drug-related lesions in these rats included renal tubular cell karyomegaly, cytome­galy, adenomas, gastric erosions and ileocoecocolic ulcers (Payne and Arena, 1978a; Payne and Saun­ders, 1978). Renal tubular cell karyomegaly does not increase mortality; however, continued dosing for a year or more has resulted in neoplasia of the tubular cells. Although drug-related lesions in la­boratory animals are common following long term heavy metal exposure, ileocoecocolic ulcers have not been reported with sodium aurothiomalate (Payne, 1982).

Dogs administered auranofin 1. 8 to 18mg gold/ kg/day for 3 months or 0.6 to 6.0 mg/kg/day for I year exhibited dose-related emesis, diarrhoea, and decreased food consumption and bodyweight (Payne and Arena, 1978b). The higher dose groups also had decreased haemoglobin and packed red blood cell volumes. In the dogs treated for I year, decreases in total serum protein and albumin were noted. as well as hyperplasia of thyroid tissues. A subclinical anaemia with normal bone marrow re-

Auranofin: A Preliminary Review

sponse was apparent in middle and high dose groups (Payne and Arena, 1978b).

1.7.3 Effects on Reproduction Oedema was the only major defect noted in fe­

tal offspring from pregnant rats administered aur­anofin 0.1 to 23.2mg gold/kg/day during days 6 through IS of pregnancy (Szabo et aI., 1978b). It was unclear whether the oedema was due to a di­rect effect on the embryo or was secondary to ma­ternal auranofin toxicity. Significant decreases in maternal food consumption and bodyweights, and in fetal bodyweights were also noted. Maternal mortality was 17% in the highest dose group.

Auranofin induced abortion, increased resorp­tion, decreased litter size, and fetal weight when given in a dosage of 0.1 to 22.6 mg/kg/day to preg­nant rabbits (Szabo et aI., 1978a). Dose-related de­creases in maternal food consumption occurred, and the higher dosages of aura no fin (9.3 and 22.6mg gold/kg/day) resulted in maternal death. The most prominent and constant fetal abnormalities asso­ciated with auranofin were abdominal defects such as gastroschisis and umbilical hernia. Anomalies of the brain, heart, lung and skeleton were seen less frequently.

2. Pharmacokinetics of Auranofin

The major distinctive pharmacokinetic prop­erty of auranofin is its absorption after oral admin­istration. Numerous single-dose and/or long term studies have been conducted in laboratory ani­mals, human volunteers and patients with rheu­matoid arthritis to determine the distribution and elimination characteristics of this gold compound.

Serum, plasma and whole blood gold concen­trations have been determined by radioisotopic and atomic absorption spectrophotometric techniques, while the more sensitive carbon rod atomisation procedure has been used in both in vitro and in l'il'O erythrocyte and lymphocyte binding studies.

Data on the effects of age, renal insufficiency and hepatic dysfunction on the pharmacokinetics of auranofin are incomplete or lacking. Some phar-

393

macokinetic properties of auranofin and other gold antirheumatic agents are listed in table IV.

2.1 Absorption

Auranofin contains aurous gold, which is sta­bilised by dual sulphur and phosphorus ligands. The molecule is therefore hydrophobic rather than hy­drophilic, and carries no ionic charge. These prop­erties facilitate the absorption of the compound fol1owing oral administration (Lorber, 1982; Stote et aI., 1983; Sutton et aI., 1983).

Auranofin is rapidly but incompletely absorbed after oral administration. The use of intravenous and oral 195Au-labelled auranofin in dogs has sug­gested that approximately 25% of an oral dose is absorbed (Gottlieb, 1982, 1983). Model-dependent absorption estimates in man have averaged ap­proximately 24% (range 15 to 38%) of the oral dose administered (Blocka et aI., 1981, 1982; Furst et aI., 1982).

Weisman et al. (1980) assessed the movement of auranofin in the intestinal tract of healthy volunteers and rheumatoid arthritis patients with a triple lumen intestinal infusion apparatus in con­junction with a non-absorbable radio-label1ed marker dilution technique. It was unclear whether transmucosal absorption occurred. The findings were most consistent with 'loose' reversible ad­sorption of auranofin onto the enteric cel1 surface, with subsequent elution into intestinal fluid. The precise location and mechanism of auranofin ab­sorption remains unknown (Bernhard, 1982a).

2.2 Plasma Concentrations

Gold concentrations following single-dose and maintenance auranofin administration have been determined using radioisotopic techniques (Blocka et aI., 1980, 1981, 1982; Furst et aI., 1982) and the atomic absorption spectrophotometric methods described by Lorber et al. (1968). The serum of healthy subjects not treated with gold-containing compounds contains less than 0.05 ng/ml of gold (Gottlieb, 1982, 1983). Optimally, pharmacokin­etic studies of auranofin should include assessment

Auranofin: A Preliminary Review 394

Table IV. Some important pharmacokinetic properties of auranofin and other widely used chrysotherapeutic agents in man (data

from Australian National Drug Information Service. 1982: Bandilla et aI., 1982; Blocka, 1983; Blocka et aI., 1980, 1982; Blocka and Landaw, 1983; Furst et aI., 1982; Gerber et al., 1972; 1974; Goobar and Horton, 1983; Gottlieb, 1980, 1982, 1983; Gottlieb et aI., 1974; Herrlinger, 1983; Herrlinger et al., 1982; Homma et al., 1982; Jessop and Johns, 1973; Lorber, 1980; Lorber et al., 1973; Mascarenhas et al. 1972; Pedersen and Graabaek, 1980; Rubenstein and Dietz, 1973; Smith et aI., 1973; Stote et aI., 1983; Van de

Stadt and Abbo-Tilstra, 1980)

Pharmacokinetic variable

Time to reach peak blood/serum concentrations of gold (hours)

Time to reach steady-state serum concentrations of gold (weeks)

Range of usual steady-state serum concentrations of gold (ltg/ml)

Apparent volume of distribution plasma compartment (L)

Protein binding (%)

Blood cell distribution (%)

Synovial fluid/serum or whole blood gold ratio

Route of excretion (% of total) renal enteric

Urinary clearance (ml/min)

Enteric clearance (ml/min)

Half-life (days)

initial serum

terminal serum total body terminal

Auranofin

1-1.5

8-12

0.3-1.0

60

40

1 : 1.7

'" 12

'" 88

0.075-0.305C

0.035-0.551c

O.17d

17d-25.5" 57.6d -80.9"

Sodium aurothiomalate

1-6

6-12

1-5

4.95-9.34"

'" 95

0-37

1 : 1.8

60-90 10-40

0.1-0.2

4.5-7.5d.e

10-35d

30-168e

Aurothioglucose

4-13

6-15

1-5

85-95

10-35b

60-90 10-40

0.1-0.2

'" 25" Up to 168e

a Initial apparent volume of distribution calculated from serum clearances; not corrected for protein binding. b This range of blood cell distribution only found in up to 45% of patients tested. c Calculated on basis of 70kg bodyweight. d Following single dose. e Following long term, multiple-dose therapy.

of both blood and serum gold concentrations (Haf­strom, 1983; Walz et aI., 1979b). During auranofin treatment, gold concentrations in plasma or serum have been virtually identical (Gobblieb and Gray, 1980); whole blood gold concentrations may be higher or lower depending upon the patient's hae­matocrit.

In patients with rheumatoid arthritis, mean peak plasma concentrations of 0.066 to 0.23p,g 195 Au/ml were attained 102 to 120 minutes following a single 6mg dose of radio labelled auranofin (Blocka et aI., 1980, 1982), whereas a mean peak plasma concen­tration of O,085p,g '95Au/ml occurred 72 minutes

after a 6mg dose of radio-labelled auranofin was administered to patients who had been treated with auranofin 3mg twice daily for 6 months (Blocka et aI., 1982).

Steady-state serum or whole blood gold concen­trations are achieved after 8 to 12 weeks of con­tinuous auranofin therapy (Bandilla et aI., 1982; Calin et aI., 1982; Champion et aI., 1982; Furst et aI., 1982; Goobar and Horton, 1983; Homma et aI., 1982). Plasma gold concentrations following at least 12 weeks of auranofin 2 to 9mg daily were 0.20 to 1.0 p,g/ml, respectively (Bernhard, 1982a; Cham­pion et aI., 1981), Once plasma gold concentrations

Auranofin: A Preliminary Review

have reached plateau levels, little individual vari­ation occurs if maintenance therapy with aurano­fin is continued (Bandilla et al., 1982; Champion et al., 1981; Gottlieb, 1982).

In children (7 to II years old) with juvenile rheumatoid arthritis administered an equivalent dose (0.1 to 0.2 mg/kg/day), gold concentrations were somewhat lower than those seen in adults (Giannini et al., 1983b). There is a significant cor­relation between the daily dosage of auranofin and the resultant plasma and/or whole blood concen­trations in adults (Champion et al., 1981, 1982; Finkelstein et al., 1980) [fig. 2] and children (Gian­nini et al., 1983a), with an increase of approxi­mately 0.1 ~g/ml in mean serum gold concentra­tion for every I mg increase in daily dosage (Champion et al., 1982).

In most studies there appeared to be no corre­lation between plasma or whole blood gold con­centrations and therapeutic efficacy (Berglo[ et al., 1978; Caruso et al., 1981; Champion et al., 1981; Giannini et al., 1983a; Schorn, 1982) or the inci­dence of toxicity (Davis et al., 1981; Hafstrom, 1983) associated with auranofin therapy. It is un­clear whether the efficacy of auranofin correlates with the concentration of blood cell-associated gold (Walz et al., 1981).

E -.. 0)

..:!o § 1.0 ~ 0.9 0 0 n = 40

c: 0.8 ~ 0.7

n = 139 § 0.6 • ~ 0.5 g, 0.4 "0 0.3

n = 134 g 0.2 n = 49 iIi 0.1 •

2 3 4 5 6

Duration of administration (months)

Fig. 2. Average whole blood gold concentrations following daily doses of auranofin 1 mg ( ............ ), 2mg (0---0), 6mg ( ___ ..... ) or 9mg (0---0) in patients with rheumatoid arthritis

(after Heuer and MorriS, 1983).

395

2.3 Distribution

In laboratory animals and man the pattern of distribution of auranofin gold differs from that of parenterally administered compounds. However, the clinical significance of this is unclear, since it is not known whether it is the free gold, the frac­tion bound to albumin, or that associated with cells which is pharmacologically active (Blocka, 1983; Hafstrom, 1983) [see introduction, section I].

The intracellular distribution of auranofin has not been studied in specific detail, and there are no reports of its apparent volume of distribution.

2.3.1 Extracellular Distribution

Unbound Serum Gold U sing an analytical procedure enabling quanti­

tation of gold at concentrations as low as 0.005 /Lg/ ml, Lorber et al. (1983a) determined that unbound serum gold represented 0.6% of the total serum gold concentration (mean 0.81 /Lgfml) after auranofin administration. In patients receiving maintenance intramuscular sodium aurothiomalate, unbound serum gold concentrations represented only 0.26 and 0.20% of the pre- and post-administration total serum gold levels (mean values 0.245 and 0.520 /Lg/ml), respectively. As recent evidence (Lorber et al., 1983a) suggests that the unbound portion of the total serum gold concentration is active in sup­pressing several human immune cell functions, the lesser binding of auranofin compared with that of sodium aurothiomalate may in part explain the differences in effects of these drugs on immune cell function (see section I).

Plasma Protein Binding Distribution to plasma proteins accounted for

59.9% of the mean whole blood concentration of auranofin gold (1.25 /Lg/ml) in patients with rheu­matoid arthritis who had undergone at least 3 months of auranofin therapy (Herrlinger et al., 1982). Of the amount of auranofin gold bound to plasma proteins, 82% was bound to albumin and 18% to immune globulins. On separation of the immune globulin molecules, 4.8% was bound to iX,-

Auranofin: A Preliminary Review

globulin, 6.9% to <X2-globulin, and 6.5% to both {3-

and 'Y-globulins (Finkelstein et aI., 1976).

Synovial Fluid Distribution Auranofin penetrates into the synovial fluid of

patients with rheumatoid arthritis, the blood/ synovial fluid ratio usually approximating 1.7: 1 (Gottlieb, 1982; Gottlieb and Gray, 1980). A sim­ilar ratio is associated with parenteral gold, al­though the absolute concentrations are usually much greater (Gottlieb, 1982). In simultaneously drawn synovial fluid and whole blood samples from 7 patients treated with auranofin (varying dosages) for a mean of 18 months, gold concentrations ranged from 0 to 0.44 ILg/ml in synovial fluid, and from 0.07 to 0.55 ILg/ml in whole blood (fig. 3).

2.3.2 Blood Cell Distribution Unlike other clinically used gold compounds,

auranofin penetrates blood cell membranes con­sistently in measurable concentrations (Herrlinger

70 70

60 60

50 50

40 40

'6 0; ..:;

30 30 c 0 .~

c Q) 20 20 " c 0

" "0 (5

10 10 <!J

0 0 Whole Synovial blood fluid

Fig. 3. Concomitant synovial fluid and whole blood gold con­centrations in 11 samples from 7 patients with rheumatoid arth­

ritis (data from Gottlieb, 1982). Open symbols (0, b, 0) desig­

nate patients with multiple determinations.

396

et aI., 1982). Analysis of whole blood and/or packed washed cells disclosed that 40 to 42% of whole blood auranofin gold content was associated with circulating cellular elements (Blocka et aI., 1980; Herrlinger, 1983; Herrlinger et aI., 1981, 1982; Walz et aI., 1979b). The percentage of cell-associated auranofin gold in whole blood is dose dependent, but is apparently unaltered by transient increases or decreases in serum gold concentration changes (Walz et aI., 1981).

At whole blood gold concentrations of 2.5 and 10 ILg/ml, auranofin gold was 23 and 38%, respec­tively, bound to erythrocytes in vitro. In contrast, sodium aurothiomalate and gold keratinate (51Lg gold/ml) were not bound to erythrocytes (Herr­linger, 1983; Herrlinger et aI., 1982). In an in vivo comparison, the mean erythrocyte gold concentra­tion following the administration of auranofin 6mg daily for 2 months was greater than that following sodium aurothiomalate 20mg weekly for the same period (0.422 and 0.1181Lg gold/ml) in spite of the higher whole blood concentration seen with sod­ium aurothiomalate (2.31 vs 0.2391Lg gold/ml) [Tausch et aI., 1983]. In erythrocytes of patients treated with auranofin (section 2.3.1), 37% and 3% of the mean whole blood concentration of auran­ofin gold was distributed in the erythrocyte hae­molysate and cell membranes, respectively (Herr­linger, 1983; Herrlinger et aI., 1982). Erythrocyte haemolysate gold concentrations following treat­ment with auranofin are higher in patients who smoke, although there is no correlation between the number of cigarettes smoked and haemolysate gold concentration, as with sodium aurothiomalate (Lewis et aI., 1983).

By use of cell fractionation procedures and car­bon rod atomisation analysis, Lorber et al. (1979b) demonstrated that for each gold compound tested the magnitude of binding of gold to lymphocytes in vivo was generally proportional to the concen­tration of gold in the plasma. However, the lymphocyte gold content (0.2-10.0 X 106 atoms gold/cell) of patients treated with auranofin 6mg daily for 4 weeks (plasma gold concentration range 0.3 to 0.9 ILg/ml) was comparable with that of patients whose plasma gold concentration was

Auranofin: A Preliminary Review

much higher (4 to 7 JIg/ml) after treatment with sodium aurothiomalate. Gold has been detected in chromatin from lymphocytes of patients treated with auranofin or sodium aurothiomalate (Tausche et aI., 1983). The clinical significance of these find­ings is unknown.

Auranofin gold is bound to platelets in vitro and in vivo (Herrlinger et aI., 1982) to an extent similar to that following treatment with sodium aurothio­malate (Lorber et aI., 1979b). The effect of aur­anofin on platelet aggregation is discussed in sec­tion 1.5.1.

2.3.3 Tissue Distribution Little is known of the organ and tissue distri­

bution of gold associated with auranofin therapy (Gottlieb and Gray, 1980). Because only small amounts of gold are retained during long term therapy with auranofin (section 2.3.4), it can be ex­pected that tissue gold concentrations will be less than those associated with parenteral treatment (Gottlieb and Gray, 1980). Walz et al. (l979b) compared the gold content of rat liver, kidney, and spleen following I year's administration of aur­anofin 6.7mg gold/kg/day orally or sodium auro­thiomalate 6.06mg gold/kg/day intramuscularly. Despite nearly equivalent blood gold concentra­tions, organ gold concentrations following auran­ofin were only 1.4 to 3.0% of those found in the sodium aurothiomalate-treated rats.

Punch biopsies performed on the skin of 4 patients with rheumatoid arthritis treated with aur­anofin (total dose 945 to 3600mg over 2.3 to 2.5 years) revealed a detectable gold concentration (1 Jig/g) only in the skin of the patient with the high­est cumulative dose (Gottlieb, 1982, 1983). Similar total dosages of parenteral gold compounds have resulted in skin gold concentrations of 2.6 to 26.5 JIg/g, with concentrations correlating with increas­ing dosages (Gottlieb, 1981, 1982).

Hair and nails have only a small affinity for gold, whether administered orally or by injection (Gott­lieb, 1982). In these tissues, gold concentrations following long term auranofin therapy have been comparable with those in patients receiving long term parenteral gold treatment (Gottlieb, 1981).

397

2.3.4 Gold Retention The amount of gold retained during chryso­

therapy can be influenced by a number of factors: the dose of the agent, frequency of dosage, route of administration, the compound given, and the patient's own rate of excretion (Gottlieb and Gray, 1980). Retention can be indirectly estimated using radioisotopic balance studies. Direct quantitation of gold content in tissues or organs can be per­formed from samples taken by biopsy, at surgery, or at postmortem examination, and by use of a whole body radiation counting chamber following radioisotope administration.

Direct and indirect studies 10 days following ingestion of a single 6mg dose of 195 Au-labelled auranofin revealed that total body retention ac­counted for 15%, and cumulative faecal and urin­ary excretion for 79.7%, of the total reactivity (Blocka et aI., 1980). 100 days following adminis­tration of the single dose, less than 5% of the total reactivity was retained. In contrast, greater than 50% retention occurred 100 days after a single 50mg dose of 195Au-Iabelled sodium aurothiomalate (Blocka et aI., 1980).

It has been estimated that sodium aurothio­malate 50mg weekly for 20 weeks will result in total body retention of 300mg of elemental gold, whereas auranofin 6mg daily will result in only 59mg of elemental gold being retained over the same pe­riod. Other estimates of gold retention following auranofin 6mg daily for 6 months have been sub­stantially lower (5 to 17mg) [Furst, 1983]. Auran­ofin 2mg daily for 20 weeks was estimated to result in no retention (Gottlieb, 1979a, 1982, 1983).

2.4 Excretion

In the first 10 days after administration of a single 6mg dose of 195Au-Iabelled auranofin to 6 patients with rheumatoid arthritis, urinary and fae­cal excretion accounted for 3.7 to 5% and 70 to 76% of the total radioactivity, respectively (Blocka et aI., 1980, 1982; Furst et aI., 1982). Six months after the single dose, cumulative urinary and faecal excretion accounted for 13.5 to 15% and 88 to 89%, respectively, of the total radioactivity (B1ocka et

> Table V, Summary of open studies of auranofin (AF) in the treatment of active rheumatoid arthritis s::

"1 I" ::)

Reference Number of Dose and dosage Antirheumatic efficacyC 0 :=-. patientsb schedule of auranofin ?

[study activity duration time to articular ESR grip no, of rheumatoid > index morning onset of index strength tender/ factor ."

duration, "1

stiffness fatigue swollen ~ months]

joints S' S' I"

Bandilla et al. (1982, 126 [~ 12] 6mg daily ++ ++ 0 ++ ++ 0 +/+ ~

1983a,b) (or 3mg bid) :;.;l r1> <:

Berglof et al. (1978) 8 [3] 3mg bid ++ + ++ ++/++ ++ (j)' $!

Caruso et al. (1981, 22 [18] 3mg bid ++ ++ ++ ++ ++ ++ ++/++ 1983)

Ciompi et al. (1983) 7 [12] 3mg bid + ++ 0 ++ + +

Ghozlan et al. (1983) 87 [3-12] 3mg bid ++ ++ ++ ++ ++ ++ ++/++

Goobar and Horton 10 [12] 3mg bid x 12-16 weeks, ++ ++ ++ ++ ++ ++/++ + (1983) then 4 or 7mg daily,

depending upon response to treatment

Hafstrom (1983) 17 [12] 6mg daily or 3mg bid for ++ ++ ++ 0 6 months, then 3mg daily to a random group of responders

Homma et ai, (1982) 47 [6] 3mg bid ('mostly') ++ ++ ++ ++ ++ ++/++

Hunt and Holt (1981, 14 (12] 4mg daily, increased to + + -/+ + 1983) 6mg daily after 4 months,

and 8mg daily after 4 additional months, depending on clinical and/or laboratory response

Lorber (1980) 14 [12] 3mg bid ++ 0 + ++/++ 0

Meyers (1979)" 12 [3] 4mg daily + + +/+ 10 [3] 6mg daily + + +/+

w 'C> 00

Auranofin: A Preliminary Review

+ 00+

+ + + + --++ +" + + "I +

+ + + 0

+ + + 0 +

+ + + +

S2. +

+ + + + + +

+ +

E CD E

~ a. .5

I B ~ c: .2'

'" ... ! I!! CI c:

! '" 9l B ~ 51 .5 g o v .s E B !E c: .2' '" 11

+ +

1 8. I!! g

j ·c CI ·iii

as .c 0

399

a\., 1980, 1982; Furst et aI., 1982). Long term treat­ment with auranofin (3mg twice daily for 21 months) resulted in a steady-state rate of urinary gold excretion of 250 to 400 /Lgjday (Caruso et aI., 1981), and urinary gold excretion has correlated highly (r = 0.739) with blood gold concentration following auranofin administration (Finkelstein et aI., 1980; Gottlieb, 1979b; Homma et aI., 1982) . The major portion of faecal excretion of a single dose of auranofin occurs within the first 4 days after administration in man (Blocka et aI., 1980). On the basis of human studies (Gottlieb and Gray, 1980), and those in rats (lntoccia et aI., 1982), the high faecal gold content associated with auranofin administration is principally due to incomplete ab­sorption, although mucosal adsorption with sub­sequent sloughing into the lumen of the gut and secretion of gold through the intestinal wall and via the biliary tract are probably contributory. The lat­ter possibilities are supported by the finding in man that the excretion of auranofin gold is delayed sev­eral days when compared with simultaneously ad­ministered stool markers (Blocka et aI., 1981).

Renal clearance of auranofin has varied be­tween 0.064 and 0.26 ml/h/kg and enteric clear­ance between 0.03 and 0.47 ml/h/kg (Blocka et aI., 1982; Furst et a\., 1982).

The initial serum half-life of auranofin in 6 patients with rheumatoid arthritis administered a single 6mg radio labelled dose was about 4 hours (Blocka and Landaw, 1983), whereas the terminal plasma half-life of a single 6mg radiolabelled dose was 17 and 25.5 days before and after 6 months' treatment with auranofin 6mg daily. In the same patients, mean terminal total body half-life was 57.6 and 81 days before and after long term dosing (Blocka et a\., 1982). Similar values were recorded by other investigators (BerglOf et a\., 1978; Blocka et a\., 1980, 1981; Gottlieb and Gray, 1980).

3. Therapeutic Trials

Auranofin has been studied in open trials and in a limited number of comparative trials in patients with active rheumatoid arthritis. The need for long term study of a disease-modifying drug in

Auranofin: A Preliminary Review

+ 00+

+ + + + + +" :t +" + I +

+ + + 0

+ + + 0 +

+ + + +

S2. +

+ + + + + +

+ + x ~ ",CD ='C

~ ~ ~.~ ~ x ~ ~ "'. ~ x~l5-g

'C-,=III .?:'e»-UJ

~ ~ ~~~~:a C) C) C)c:c~~ ~ ~ ~~~MO

N :€ CL ..- - ~ £ is !.~~§~ M M It) Ii' '5 N .......... co _

~ M '" CIO - '" :; ~ 'CO; ~ ~ 5 S; II) en .v ..... ca !:.. c: ";;" CD E ~:E :::I 0 (/) c: C) -'= .- c: ~ ~ ~ ~

c CD E

~ a. .5

I B ~ c: .2' Ul ~

! I!! C)

c:

! Ul 9l B ~ 51 .5 g o v .s c B !E c: .2' Ul II

+ +

1 8. I!! g

j '2 C) 'iii is

c: ~ o c: i ~ ::sq:: 'iii '2 ~ .~ ~1S III c: u •

. == 'E ",CD CD '2 CD E 0-,= CD

- > E c: 0

S~~ 1:; -8 .-III :;, II igg+ .£l .- +.: III Ul c: c: C II) .- CD E 'C+,CD CD III > 5~[ a.°E e i .-",..0 0 '0 E c: .a ::I II OOZo

III ..0 u

399

aI., 1980, 1982; Furst et aI., 1982). Long term treat­ment with auranofin (3mg twice daily for 21 months) resulted in a steady-state rate of urinary gold excretion of 250 to 400 /Lgjday (Caruso et aI., 1981), and urinary gold excretion has correlated highly (r = 0.739) with blood gold concentration following auranofin administration (Finkelstein et aI., 1980; Gottlieb, 1979b; Homma et aI., 1982). The major portion of faecal excretion of a single dose of auranofin occurs within the first 4 days after administration in man (Blocka et aI., 1980). On the basis of human studies (Gottlieb and Gray, 1980), and those in rats (lntoccia et aI., 1982), the high faecal gold content associated with auranofin administration is principally due to incomplete ab­sorption, although mucosal adsorption with sub­sequent sloughing into the lumen of the gut and secretion of gold through the intestinal wall and via the biliary tract are probably contributory. The lat­ter possibilities are supported by the finding in man that the excretion of auranofin gold is delayed sev­eral days when compared with simultaneously ad­ministered stool markers (Blocka et aI., 1981).

Renal clearance of auranofin has varied be­tween 0.064 and 0.26 ml/h/kg and enteric clear­ance between 0.03 and 0.47 ml/h/kg (Blocka et aI., 1982; Furst et aI., 1982).

The initial serum half-life of auranofin in 6 patients with rheumatoid arthritis administered a single 6mg radio labelled dose was about 4 hours (Blocka and Landaw, 1983), whereas the terminal plasma half-life of a single 6mg radiolabelled dose was 17 and 25.5 days before and after 6 months' treatment with auranofin 6mg daily. In the same patients, mean terminal total body half-life was 57.6 and 81 days before and after long term dosing (Blocka et aI., 1982). Similar values were recorded by other investigators (BerglOf et aI., 1978; Blocka et aI., 1980, 1981; Gottlieb and Gray, 1980).

3. Therapeutic Trials

Auranofin has been studied in open trials and in a limited number of comparative trials in patients with active rheumatoid arthritis. The need for long term study of a disease-modifying drug in

Auranofin: A Preliminary Review

rheumatoid arthritis was recognised in a minority of studies in which treatment continued for at least 2 years. Most studies, however, have been con­ducted for 12 months or less.

The criteria for assessing disease activity and therapeutic efficacy have usually included articular index, walk time, grip strength, duration of morn­ing stiffness, pain, physical wellbeing, global as­sessment by patient and/or physician and altera­tions in erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor titre, and immunoglob­ulin concentrations. Auranofin in fixed dosages has been compared with placebo (section 3.1.3), sod­ium aurothiomalate (gold sodium thiomalate) [sec­tion 3.1.4], D-penicillamine (section 3.1.5), hy­droxychloroquine (section 3.1.5) and levamisole (section 3.1.5). A preliminary study assessed the value of auranofin in the treatment of juvenile rheumatoid arthritis (section 3.2).

3.1 Rheumatoid Arthritis

It is well established that the natural course of rheumatoid arthritis is variable and unpredictable and frequently characterised by spontaneous re­missions and exacerbations. Also, drug response may be greatly influenced by psychological factors. Therefore the full clinical evaluation of a new anti­rheumatic agent, which is perhaps capable of in­ducing remission, requires long term well-designed comparative therapeutic trials in homogeneous patient groups (Lipsky, 1983).

3.1.1 Open Studies Although open studies involving small numbers

of patients (e.g. BerglOf et aI., 1978; Ciompi et aI., 1983; Meyers, 1979) can provide little definitive data on the therapeutic efficacy and overall toler­ability of a drug used to treat rheumatoid arthritis, long term open trials can provide useful data when large numbers of patients are involved.

A vailable reports of open trials with auranofin have involved only relatively small numbers of patients (mostly female, as is typical of a rheu­matoid arthritis population) with mild to moder­ately severe disease (average functional and ana-

400

tomical stage II) of about 6 years' duration. Although most studies have been conducted for around 12 months or more, others have been too brief to provide useful data on the efficacy of a potentially disease-modifying antirheumatic agent.

In most instances, the study protocol allowed the concomitant administration of non-steroidal anti-inflammatory and/or analgesic drugs with aur­anofin, and in several studies patients who were receiving maintenance corticosteroid treatment participated in the study. Patients who had re­ceived previous courses of remission-inducing agents (parenteral gold compounds, chloroquine, D-penicillamine and cytotoxic agents) were admit­ted to at least 7 open studies (Bandilla et aI., 1982; Ciompi et aI., 1983; Ghozlan et aI., 1983; Haf­strom, 1983; Homma et aI., 1982; Hunt and Holt, 1983; Noguera et aI., 1983). Although these drugs had been withdrawn 3 to 6 months before comm­encing treatment with auranofin, Bandilla et al. (1982) reported detectable serum gold in 17 (23%) of 74 patients at the start of their trial.

Open studies (table V) have suggested that aur­anofin is an effective antirheumatic drug, as evi­denced by improvement in articular index, activity index, duration of morning stiffness, and erythro­cyte sedimentation rate, and a decreased require­ment for concomitant antirheumatic drug therapy. As with other chrysotherapeutic agents, response to auranofin (2 to 6mg daily) is delayed. Changes in articular index and erythrocyte sedimentation rate have sometimes occurred only after 36 to 48 weeks of treatment (Bandilla et aI., 1982; Noguera et aI., 1983).

The effect of auranofin on erythrocyte sedimen­tation rate has been variable, with approximately equal numbers of studies reporting either a sig­nificant decrease or no change. However, in 2 of the 5 studies reporting no change in erythrocyte sedimentation rate, duration of treatment was only 3 months. Rheumatoid factor titres were also in­consistently influenced by auranofin. Recent stud­ies (Noguera et aI., 1983; Schorn, 1982) have re­ported significant decreases in mean serum IgA, IgG, and IgM concentrations following 3 to 12 months' treatment with auranofin.

Auranofin: A Preliminary Review

About half and two-thirds of patients treated by Meyers (1979) and Weisman and Hannifin (1979), respectively, exhibited a favourable clinical re­sponse to auranofin, but there was no correlation between response and steady-state blood gold con­centrations (Weisman and Hannifin, 1979). How­ever, Hafstrom (1983) noted correlations between serum gold concentration and reduction in activity index after 24 weeks' treatment with auranofin, and between maximum serum gold concentration and reduction in activity index at the end of auranofin treatment (up to I year's duration).

A daily dosage of 6mg, administered as a single dose or in 2 divided doses, was employed by Haf­strom (1983) who indicated that once-daily admin­istration was associated with no loss of efficacy, and that initial response could be maintained with half of the dosage given during the first 6 months of the study. Similarly, in the majority of the patients treated by Goobar and Horton (1983), the initial improvement seen following auranofin 3mg twice daily for 3 to 4 ~onths was maintained with reduced daily doses (usually 4mg).

Recent open studies have suggested that aur­anofin may be particularly useful for active disease of recent onset that has not progressed beyond ana­tomical stages I or II (Bandilla et aI., 1983b; Ciompi et aI., 1983; Homma et aI., 1982; Schorn, 1982, 1983).

Withdrawal of auranofin treatment due to inef­ficacy or side effects has been necessary in 0 to 33% of patients in the open studies, but there is little evidence of any clear association between the in­cidence or severity of side effects (section 4) and serum or blood gold concentrations (Hafstrom, 1983; Weisman and Hannifin, 1979).

The progression of erosive disease during aur­anofin therapy was also studied in the open trials of Bandilla et al. (1982) and Homma et al. (1982). The results are discussed in section 3.1.6.

3.1.2 Dose Establishment Studies Several open and double- or single-blind studies

have been conducted to determine the dosage of auranofin which provides optimum therapeutic benefit with minimum toxicity (table VI).

401

In most of these studies, female patients have predominated, and subjects had active rheumatoid arthritis of 3 to 4 years duration. Distribution of patients according to functional and anatomical status was detailed in only I report (Bernhard, I 982b), where most patients were offunctional class II, anatomical stage class II. Some studies excluded patients who had previously been treated with gold compounds or other disease-modifying agents (Baldassare et aI., 1980; Calin et aI., 1982; Cham­pion et aI., 1982, 1983), while including those re­ceiving systemic or intra-articular corticosteroids. Although approximately 26% of the patients stud­ied by Bernhard (1 982b ) were receiving mainten­ance systemic corticosteroids, they were evenly dis­tributed between the high- and low-dose auranofin treatment groups, the dosage of corticosteroid was kept constant for the initial 12 weeks of the study, and no subsequent increase in their dosage was permitted. Auranofin has no direct analgesic activ­ity, and therefore concomitant administration of non-steroidal anti-inflammatory drugs was permit­ted in all studies. Champion et al. (1982) allowed drug or dosage changes in non-steroidal anti-in­flammatory regimens when side effects became troublesome.

In the dose-establishment studies, antirheu­matic efficacy was most often manifested by de­creases in duration of morning stiffness and num­ber of tender or swollen joints. Only I study reported improvement in activity index (Schatten­kirchner and Delattre, 1983), and only 2 studies (Bernhard, 1982b; Schattenkirchner and Delattre, 1983) demonstrated improvement in articular in­dex. Decreases in 19A and IgM occurred at 3 and 6 months in patients receiving auranofin 6mg daily, but only after 6 months in patients treated with 2mg daily. Similarly, IgG decreased after 6 months in patients receiving 6mg daily, but not at all in the group treated with 2mg daily (Bernhard, 1982b). Only Finklestein et al. (1980) reported significant decreases in rheumatoid factor titre.

Generally a dosage of auranofin 6mg daily was compared with 2mg or 3mg daily, and no signifi­cant differences between the therapeutic efficacy of the dosage regimens were found (Baldassare et aI.,

Table VI. Summary of studies comparing different dosage regimens of auranofin (A F) in the treatment of active rheumatoid arthritis >-~ .., Ol

Reference Number of Study design Antirheumatic efficacyd ::l 0

patientsb Dose and dosage ~

duration time to grip no. of articular rheuma- index of ESR relative clinical ? [study schedule of

morning onset of strength tender/ index toid function' efficacy of regimens >-duration, auranofin '"tl months] stiffness fatigue swollen factor studied ..,

2 joints titre 3'

:;. Baldassarre et al. 24 [3-12] dbC Ol

,:;:l (1980)a Group I: 3mg bid + + No conclusions

~ Group II: 1 mg bid stated '" <: ". Bernhard (1982b) 230 [6] dbC ~

[also see Group I: 2mg qd ++ ++ ++ ++/++ ++ + + 2mg qd "" 6mg qd Weiss, 1983] Group II: 6mg qd ++ ++ ++ ++/++ ++ + +

Calin et al. (1982) 106 [6] dbC

[also see Group I: 1 mg qd 0 0 9mg qd > lmg qdO

Weiss, 1983] Group II: 9mg qd

Champion et al. 12 [6] sb, r (1982) All pts 6mg qd x 1

month, then Group I: 2mg qd ++ 0 ++/++ 0 ++ ++ 2mg qd "" 3mg qd

Group II: 3mg qd ++ ++ ++/++ 0 ++ 0

Champion et al. 31 [6] db (1983) All pts lmg qd

x 1 month, then Group I: 4mg qd ++ ++ ++/++ ++ ++ 4mg qd = 6mg qd

Group II: 6mg qd ++ ++ ++/++ ++ ++ = 8mg qd

Group III: 8mg qd ++ ++ ++/++ ++ ++

Finklestein et al. 28 [3] op (1980) Group I: 2mg qd + +/+ ++ + 3mg bid or tid >

Group II: 4mg qd 2mg qd or 4mg qd

Group III: 3mg bid Group IV: 3mg tid

Gottlieb et al. 18 [6] db (1980a,b)a Group I: 3mg bid x 8 ++ ++/++ + 0 lmg qd "" 3mg qd

wks, then 3mg qd x 18 wks

.... 0 N

Auranofin: A Preliminary Review

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403

1980; Bernhard, 1982b; Champion et aI., 1982, 1983; Gottlieb et aI., 1980a). This could be attrib­utable in part to the small numbers of patients studied by Baldassare et al. (1980) and Gottlieb et al. (1980a,b), but 230 patients were evaluated by Bernhard (1982b). Alternatively, the 6- to 12-month treatment periods may have been too brief to fully assess the relative efficacy and toxicity of the dif­ferent treatment regimens. Champion et al. (1983) analysed 6-month data by use of multivariate pro­cedures incorporating trend analysis and found no significant relationship between the dose of aur­anofin administered or steady-state serum gold concentration and antirheumatic response. Failure of the technique to discriminate between the 3 dos­ages was attributed the narrow dosage range (4 to 8mg) being investigated.

Diarrhoea was the most common side effect re­ported and appeared to be dose related (Bernhard, 1982b; Calin et aI., 1982), while dermatological re­actions (usually rash) were most likely to result in withdrawal of auranofin treatment (Bernhard, 1982b; Calin et aI., 1982; Champion et aI., 1982). In the comparison by Bernhard (l982b), the with­drawal rate due to side effects was similar in patients treated with either 2mg or 6mg daily, but adverse gastrointestinal reactions occurred more often with the higher dosage.

Withdrawals due to drug inefficacy have ranged from 25 to 57% (Calin et aI., 1982; Champion et aI., 1982) with an apparent lack of efficacy asso­ciated with low dosages of auranofin (I to 3mg daily) in some studies (Calin et aI., 1982; Gottlieb et aI., I 980a,b). However, other investigators (e.g. Bernhard, 1982b) reported lack of response in a similar proportion of the 230 patients treated with 2mg (40%) and 6mg (39%) daily. Although the re­sponse to auranofin, as with other chrysotherapeu­tic agents, may show considerable interindividual variation, auranofin 6mg daily has been generally well tolerated (Bernhard, 1982b; Champion et aI., 1982; Gottlieb et aI., I 980a,b ) and associated with a more rapid therapeutic response than lower dos­ages (Bernhard, 1982b). Of the 4 dosages (2, 4, 6 and 9mg daily) studied by Finkelstein et al. (1980), 6mg daily was considered to be the most fitting

Auranofin: A Preliminary Review

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1980; Bernhard, I 982b; Champion et aI., 1982, 1983; Gottlieb et aI., 1980a). This could be attrib­utable in part to the small numbers of patients studied by Baldassare et al. (1980) and Gottlieb et al. (1980a,b), but 230 patients were evaluated by Bernhard (1982b). Alternatively, the 6- to 12-month treatment periods may have been too brief to fully assess the relative efficacy and toxicity of the dif­ferent treatment regimens. Champion et al. (1983) analysed 6-month data by use of multivariate pro­cedures incorporating trend analysis and found no significant relationship between the dose of aur­anofin administered or steady-state serum gold concentration and antirheumatic response. Failure of the technique to discriminate between the 3 dos­ages was attributed the narrow dosage range (4 to 8mg) being investigated .

Diarrhoea was the most common side effect re­ported and appeared to be dose related (Bernhard, 1982b; Calin et aI., 1982), while dermatological re­actions (usually rash) were most likely to result in withdrawal of auranofin treatment (Bernhard, 1982b; Calin et aI., 1982; Champion et aI., 1982). In the comparison by Bernhard (l982b), the with­drawal rate due to side effects was similar in patients treated with either 2mg or 6mg daily, but adverse gastrointestinal reactions occurred more often with the higher dosage.

Withdrawals due to drug inefficacy have ranged from 25 to 57% (Calin et ai., 1982; Champion et ai., 1982) with an apparent lack of efficacy asso­ciated with low dosages of auranofin (1 to 3mg daily) in some studies (Calin et aI., 1982; Gottlieb et aI., J980a,b). However, other investigators (e.g. Bernhard, 1982b) reported lack of response in a similar proportion of the 230 patients treated with 2mg (40%) and 6mg (39%) daily. Although the re­sponse to auranofin, as with other chrysotherapeu­tic agents, may show considerable interindividual variation, auranofin 6mg daily has been generally well tolerated (Bernhard, 1982b; Champion et ai., 1982; Gottlieb et ai., 1980a,b) and associated with a more rapid therapeutic response than lower dos­ages (Bernhard, 1982b). Of the 4 dosages (2, 4, 6 and 9mg daily) studied by Finkelstein et al. (1980), 6mg daily was considered to be the most fitting

Auranofin: A Preliminary Review

initial dosage for subjective and objective clinical improvement.

As with most other antirheumatic agents, in­dividual dosage adjustments may be necessary with auranofin (Weiss, 1983). However, auranofin 6mg daily may be an appropriate initial dose in most patients with rheumatoid arthritis.

3.1.3 Auranofin Compared with Placebo In placebo-controlled studies the clinical effi­

cacy of auranofin has generally been shown to be superior to that of placebo. In two 6-month double­blind parallel studies of 152 and 18 patients [Wen­ger et aI., 1983a (see also Katz et aI., 1982) and Morteo et aI., 1983, respectively] and a 3-month single-blind crossover study of 8 patients (Finkel­stein et aI., 1976), auranofin 3mg 2 or 3 times daily significantly decreased the number of tender and swollen joints and the duration of morning stiff­ness, and increased grip strength compared with placebo. Auranofin 3mg twice daily also produced a significant decrease in IgA, IgG, IgM and eryth­rocyte sedimentation rate 3 and 6 months after commencement oftherapy (Finkelstein et aI., 1976; Wenger et aI., 1983a). Another 6-month, random­ised double-blind parallel comparison of auranofin and placebo has been reported (Palmer et aI., 1983). In this study, the high dropout rate (50%) in both patient groups (each consisting of 10 patients) pre­cluded any meaningful statistical analysis of effi­cacy data; however, a greater number of intra-ar­ticular corticosteroid injections were required by patients receiving placebo than those administered auranofin. Neither agent reduced patient depend­ability on non-steroidal anti-inflammatory agents. In the study by Wenger et al. (1983a), side effects developed in about 58% of patients treated with auranofin and in approximately 27% receiving pla­cebo, and necessitated treatment withdrawal in 5% and 3%, respectively.

In a multicentre double-blind study of 244 patients (Abe et aI., 1984), auranofin 6mg daily for 24 weeks resulted in greater mean 'global efficacy' (p < 0.00 I) and 'global utility' (p < 0.05) ratings than did placebo treatment. 'Global safety' ratings for each treatment were similar, with 37.1% and

404

26.4% of auranofin and placebo-treated patients experiencing side effects, respectively.

3.1.4 Comparisons with Sodium Aurothiomalate A number of open, placebo-controlled, and

blinded comparisons of auranofin and sodium aurothiomalate (gold sodium thiomalate) have been reported (table VII). Unfortunately, most of these comparative studies have been published in ab­stract form only, or as preliminary findings from a trial still in progress. Therefore, little definitive data regarding efficacy and tolerability associated with these 2 agents are available. Full reports of these trials and other well-designed comparisons between auranofin and sodium aurothiomalate will be necessary before the relative role of these 2 drugs in the treatment of rheumatoid arthritis is known.

The comparative studies of auranofin and sod­ium aurothiomalate have been conducted with patient populations averaging 70 patients each (range 24 to 208). Generally, auranofin 6mg in single or divided daily doses has been compared with sodium aurothiomalate 50mg weekly, and these medications have been added to pre-existing regimens of non-steroidal anti-inflammatory drugs. Most of the studies have been designed to be 1 to 2 years in duration, but results reported to date have usually described the safety and efficacy as­sociated with each agent only during the initial 6 to 12 months of therapy or in only a portion of the total number of patients.

Generally, patients were predominantly female (male to female ratio 1 : 2 to 3), 45 to 55 years of age, and had symptoms of classic or definite rheu­matoid arthritis of 5 to 6 years duration. Although minor differences in severity of duration of disease were reported between treatment groups, none was statistically significant. Three studies (Barraclough et aI., 1982; Schattenkirchner et aI., 1982; Ward et aI., 1983a,b,c,d) allowed participation by patients taking systemic corticosteroids (although dosages of these agents were limited), and another (Menard et aI., 1982) permitted restricted use of intra-arti­cularly injected corticosteroids during treatment with auranofin or sodium aurothiomalate. Menard

Auranofin: A Preliminary Review

et al. (1982) and Smith et al. (1983) specifically ex­cluded patients who had received rheumatoid­remitting agents within the previous 6 months, whereas Ward et al. (I 983a,b,c,d) excluded patients who had previously received gold compounds or cytotoxic agents, and Davies et al. (1983) excluded those treated with disease-modifying agents or steroids.

In the studies where statistical analysis of patient response was presented, sodium aurothiomalate was at least as effective as auranofin as evidenced by the level of significance of the changes in the as­sessment criteria (Komatsubara et aI., 1984; Lee, 1981; Lewis et aI., 1982, 1983; Menard et aI., 1982; Smith et aI., 1983; Ward et aI., 1983b,c,d). Lee (1981) reported that response to auranofin was more rapid than to sodium aurothiomalate [7.7 or 6.0 weeks (depending on dose of auranofin) versus 9.4 weeks], although Lewis et a1. (1982, 1983) noted an earlier response in the patients treated with sod­ium aurothiomalate. The conflicting nature ofthese data was probably due to differing criteria used to gauge response: Lee defined response time as the occurrence of 'clinical symptomatic improvement' whereas Lewis and co-workers used more objective parameters (decreases in erythrocyte sedimenta­tion rate, C-reactive protein, and pain scores) to assess duration of response. Although many para­meters of disease activity were usually measured, the efficacy of either gold compound was most often manifested by decreases in duration of morning stiffness, pain scores, number of tender joints, joint tenderness score, activity and articular indices, and improvements in physician's global assessment and feeling of wellbeing (Lewis et aI., 1983; Menard et aI., 1982; Smith et al., 1983; Ward et aI., 1983b,c,d). Both auranofin and sodium aurothiomalate de­creased erythrocyte sedimentation rate, rheuma­toid factor titre and C-reactive protein in several studies; however, the decreases occasionally reached a higher level of statistical significance following sodium aurothiomalate therapy (Keegan et aI., 1983; Lewis et aI., 1982; 1983; Smith et aI., 1983).

Unfortunately, few comparative trials have re­ported the rates of remission associated with the parallel administration of these gold compounds.

405

Lee (1981) reported an approximate 25% remission rate in both auranofin and sodium aurothiomalate treatment groups. These data may not be truly rep­resentative, however, since the number of patients in each treatment group was small (8) and the treatment time was relatively brief (26 weeks). Smith et al. (1982, 1983) determined the severity of disease at 6-monthly intervals in patients treated with auranofin or sodium aurothiomalate for 18 months. At 6 and 12 months, when the treatment groups were largest and most representative, the remission rate in the sodium aurothiomalate-treated patients was 2 and 1.7 times, respectively, that in patients receiving auranofin. After 12 months of treatment, there were no longer any patients with severe disease in either group.

Withdrawals because of inefficacy have gener­ally been equal in the two treatment groups, al­though Menard et a1. (1982) reported that with­drawals were twice as frequent with auranofin as with sodium aurothiomalate, and Ward et ai. (1983a,b,c,d) noted 5 withdrawals due to inefficacy in the auranofin group and none in the patients treated with sodium aurothiomalate.

In the dosages administered in the comparative studies, auranofin and sodium aurothiomalate were generally associated with the same overall inci­dence of side effects (Davies et aI., 1983; Lee, 1981; Kaik et aI., 1983; Menard et aI., 1982). However, side effects necessitating withdrawal of treatment were generally more frequent with sodium auro­thiomalate than with auranofin (table VII; section 4). Mucocutaneous side effects were more frequent and/or severe within the patient groups treated with sodium aurothiomalate (Jamer et aI., 1983; Kaik et aI., 1983; Menard et aI., 1982; Smith et aI., 1982; Ward et aI., 1983a,b,c,d), whilst gastrointestinal side effects were more frequent during auranofin therapy (Jamer et aI., 1983; Menard et aI., 1982; Schatten­kirchner et aI., 1982; Smith et aI., 1983).

Patients with rheumatoid arthritis previously controlled by sodium aurothiomalate have been 'crossed over' to treatment with auranofin with varying results. The transfer (usually from sodium aurothiomalate 50mg every 2 to 4 weeks to aur­anofin 3mg twice daily) was not associated with

Table VII. Summary of non-blinded, placebo-controlled, and blinded comparative studies of auranofin (AF) and sodium aurothiomalate (ATM) in the treatment of active ;I>

'" rheumatoid arthritis ~ :3 0

Reference No. of patients Study Dose and dosage No. of patients and F.lelative Relative number No. of ::tl ?

(planned study designC schedule duration at time of antirheumatic and/or severity of withdrawals ;I>

duration) efficacy evaluation efficacy side effects due to side 'tl

effects a 3'

Non-blinded comparisons S' I»

Keegan et al. (1983) 37 pts AF 3mg bid 25 pts at 6 months AF < ATM e AF 1 .,' ... '<

(1 year) ATM 50mg q wk ATM 3 :;tl ... x 20 wks, then <

iii' 50mg q month ~

Komatsubara et al. 83 pts AF 6mg qd 83 pts at 24 weeks AF", ATM AF < ATM AF 2 (1984)8 (Not specified) ATM 10-50mg ATM 8

q 1-2 wks

Lee (1981) 24 pts GRP I: AF 3mg bid 24 pts at 26 wks AFt '" ATM AFt", ATM AF 0 [also Moon et aI., 1981]8 (26 weeks) x 4 wks, then 2mg ATM 1

bid x 22 wks GRP II: AF 3mg bid x 26 wks GRP 111: ATM 10mg q wk x 2 wks, 25mg 3rd wk, then 50mg weekly thereafter

Menard et al. (1982)b 120 pts AF 3mg bid Study completed AF < ATM AF < ATM AF 7 [also Thompson et aI., (2 years) ATM 50mg q wk ATM17 1981,1983]0 x 20 wks, then

50mg q month to 52 weeks

Smith et al. (1983) 60 pts AF 3mg bid 29 pts at 96 wks AF';; ATM AF < ATM AF 0 [also Smith et aI., 1982]b (up to 96 weeks) ATM 50mg q wk ATM 6

3rd-24th wk, then monthlyd

Tvede and Strandberg 30 pts AF 3mg bid 16 pts at 48 wks AF", ATM AF'" ATM AF = ATM (1983)b (48 weeks) ATM 50mg q wk

~ a-

Placebo-control/ed comparisons ~ ::: .,

Davies et al. (1983)b 30 pts AF 3mg bid 26 pts at 9 months AF;;' PL AF'" ATM PL 0 '" ::I

(1 year) ATM 50mg q wk x ATM;;' PL AF 0 0 ~

6 mos, then 20-50 AF '" ATM ATM 1 ?

mg q month ~ ." .,

Lewis et aI., (1982)a 90 pts AF 3mg bid 66 pts at 24 weeks AF;;' PL AF '" ATM PL 0 2

[also Lewis and Capell, (Not specified) ATM 50mg q wk ATM> PL AF 4 3' 5'

1983) AF < ATM ATM 7 '" ~ Prouse and Gumpel 30 pts r, db (PL AF 3mg bid 22 pts at 1 year AF> PL AF'" ATM PL 0 it!

'" (1983)b (2 years) com pari- ATM 50mg q wk ATM> PL AF 3 <: ;:;).

[also Prouse et aI., son only) AF < ATM ATM 4 ~ 1981)b

Ward et al. (1983b) 208 pts r, db AF 3mg bid 161 pts at 20 weeks AF> PL AF < ATM PL 1 [also Ward et aI., (21 weeks) ATM 50mg q wk ATM> PL AF 5 1983c,d; Williams, 3rd-2Oth wkd AF '" ATM ATM 22 1982)a.b

Blinded comparisons

Barraclough et al. (1982)b 42 pts r, sb AF 3mg bid 14 pts at 1 year .. . . AF < ATM AF 1 [also Barraclough et al. (1 year) ATM 50mg q wk ATM 6 1983)b x 20 wks, then

50mg q 3 wks

Jarner et al. (1983)b 45 pts r, db AF 3mg bid 14 pts at 1 year AF", ATM AF '" ATM AF 6

(1 year) ATM 50mg q wk ATM 9

3rd-24th wk, then q 2-4 wksd

Schattenkirchner et al. 121 pts r, db AF 6mg qd 68 pts at 48 AF '" ATM AF 17 (1982)b (1 year) ATM 50mg q wk weeks ATM 28 [also Kaik et aI., 1983; 3rd-24th wk, Muller-Fassbender et al. then monthlyd 1983; Rau et aI., 1983)b

a Study reported in abstract form only.

b Preliminary report of study still in progress.

c r = randomised; db = double-blind; sb = single-blind; PL = placebo.

d ATM 10 or 20mg 1st week, 20mg 2nd week.

e An ellipse indicates insufficient data exists for efficacy or side effect evaluations.

Efficacy and tolerability rating combining both auranofin groups. +> 0 ---l

Auranofin: A Preliminary Review

worsening of disease activity in one study (Wenger et aI., 1983b), whereas a subgroup of the patients of Berry et al. (1983) [usually those with more ac­tive disease at the commencement of treatment] withdrew from auranofin therapy due to worsening of their rheumatoid symptoms. Of the II patients of Parke et al. (1983) who were stabilised on sod­ium aurothiomalate and later switched to auran­ofin, only 4 completed 1 year of treatment. Most patients withdrew due to inefficacy or toxicity, as did the remaining patients in their second year of treatment. The side effect incidence (except aur­anofin-induced diarrhoea) in patients who toler­ated sodium aurothiomalate and continued to re­ceive the drug, generally did not differ from that in patients who had been transferred to auranofin.

Wessel and Davis (1983) administered a cu­mulative dose of at least Ig sodium aurothiomalate (mean duration of treatment not specified) to 6 patients who had failed to respond to auranofin 3mg twice daily for 20 weeks or more. Only I patient manifested modest improvement when switched to the parenteral gold compound. Al­though further studies are required, the results in this small group of patients suggest that changing from oral to parenteral gold treatment (when the former is ineffective) may not offer patients sig­nificant additional therapeutic benefit.

3.1.5 Comparisons with Other Agents Limited data are available from an interim re­

port of a 48-week, randomised, single-blind com­parison of auranofin 3mg twice daily and hydroxy­chloroquine 200mg twice daily (Bird et aI., 1983). Only a few of the 40 patients have completed the trial; however, auranofin decreased concentrations of IgM, IgG, and IgA, and both agents increased grip strength. Hydroxychloroquine also increased haemoglobin concentrations (which remained de­creased in auranofin patients) and decreased C-re­active protein, erythrocyte sedimentation rate, plasma viscosity, and platelet concentrations in a limited number of patients. Side effects have been more frequent in the auranofin group, as have been the withdrawals due to side effects or inefficacy (7 I'crsus I patient).

408

Auranofin 6mg daily has been compared with D-penicillamine 150 to 750mg daily (Astaldi et aI., 1983; Barraclough et aI., 1983; Felix-Davies et aI., 1982, 1983; Franchimont et aI., 1983; Scott and Huskisson, 1981), aurothioglucose (Van Riel et aI., 1983b,c), and levamisole 150mg weekly (Scott and Huskisson, 1981) in open and single-blind trials in­volving relatively small numbers of patients. No consistently significant differences in efficacy have been detected, with all drugs producing improve­ment in articular index, morning stiffness, joint swelling, and pain in some patients. Side effects tended to be more troublesome with D-penicillam­ine and aurothioglucose than with auranofin, and drug withdrawals due to inefficacy have occurred more commonly with auranofin.

In a randomised, single-blind study (Dequeker et aI., 1983a,b) and a double-blind multicentre trial [Khan et aI., 1983 (see also Sany et aI., 1981 )], aur­anofin 3mg twice daily was shown to have less antirheumatic activity than sodium aurothiolpro­panolsulphonate 100mg weekly. In the 40 patients of Dequeker et al. (1983a,b), auranofin caused sig­nificant improvement in duration of morning stiff­ness, number of tender and/or swollen joints, im­munoglobulin concentrations, and articular and activity indices. In addition to these parameters, sodium aurothiolpropanolsulphonate also im­proved mean pain scores and erythrocyte sedi­mentation rate. Of the 60 patients of Khan et al. (1983) treated with auranofin, only the articular in­dices and the number of swollen joints were im­proved at 12 months, while these measurements plus activity index, number of tender joints, grip strength, walk time, pain score, duration of morn­ing stiffness, time to onset of fatigue, general wellbeing, and erythrocyte sedimentation rate were improved by sodium aurothiolpropanolsulphonate. Withdrawals due to sodium aurothiolpropanolsul­phonate side effects greatly exceeded those due to auranofin in one study (11 and 1, respectively) [Dequeker et aI., 1983a,b], whereas auranofin caused more withdrawals due to side effects in the study of Khan et al. (1983) [11 vs 7 patients]. With­drawal rates due to inefficacy were approximately equal for both agents in either study.

Auranofin: A Preliminary Review

Further well-designed studies in adequate num­bers of patients are needed to determine the rela­tive efficacy and tolerability of these potentially disease-modifying drugs.

3.1.6 Effects of Auranofin on Radiographically Detected Progression of Rheumatoid Disease In rheumatoid arthritis, the radiographic find­

ings of erosion, cartilage loss, and joint destruction appear to correlate well with the clinical evaluation of the patient, and may have prognostic signifi­cance regarding the course of the disease (Genant, 1983). Although there is some evidence in favour of a 'disease-modifying' activity for injectable gold compounds and cyclophosphamide, there exists no definitive proof that any antirheumatic agent cur­rently in use is capable of preventing or retarding joint damage in rheumatoid arthritis (Iannuzzi et aI., 1983; Larsen et aI., 1983). The radiographic studies performed to assess the effects of auranofin on cartilage and/or bone loss (table VIII) have en­countered some of the same methodological diffi­culties which arose in previous studies of other antirheumatic agents (Larsen, 1983; Muller-Fass­bender, 1983). There appears to have been little or no agreement nor any accepted standards among the investigators for the location, the method of scoring, or the proper statistical analysis of joint space narrowing or osseous lesions. Also, most of the study groups were small (15 to 37 patients) and were studied over relatively brief time spans (12 to 18 months). Finally, non-steroidal anti-inflamma­tory agents and/or steroids [which also have as yet undefined effects on radiological deterioration (Iannuzzi et aI., 1983)] were administered to most patients. Therefore, the data resulting from studies to determine the radiological progression of rheu­matoid arthritis following treatment with aurano­fin must be interpreted with considerable caution.

Radiographic studies have mostly involved small to moderate numbers of patients (15 to 83), most of whom received auranofin 6mg daily in single or divided daily doses over a period of 12 to 18 months.

The most common assessment method used in the radiographic studies was that of Larsen et ai.

409

(1977), a system which involves the scoring of in­creases in bone erosion and joint space narrowing from hand and foot radiographs. To assess the pro­gression of osteoporosis in patients with rheuma­toid arthritis, Schorn (1983) determined the area index [(outside diameter of the second metacarpel bone of the right hand)2 - (the inside diameter)2 ... both measured at the bone midpoint] from hand radiographs which allowed assessment of the cor­tical bone diameter. This, in turn, is known to cor­relate well (r = 0.85) with the ash weight of bone (Exton-Smith et aI., 1969). Gofton and O'Brien (1982, 1983) and O'Brien (1981) utilised a rating system in which the erosion rates experienced prior to treatment with auranofin were used to predict the rate of erosion that would have occurred if treatment had not been given. Although the rate of erosive change predicted by the model was sim­ilar to that seen in placebo-treated patients in other clinical trials, further testing of this model under placebo-controlled conditions is required to deter­mine its validity.

In several studies (Gofton and O'Brien, 1982, 1983; Homma et aI., 1982; O'Brien, 1981) the data of the effects of auranofin have been compared with those derived from earlier trials (The Cooperating Clinics Committee of the American Rheumatism Association, 1973; Empire Rheumatism Council, 1960) with sodium aurothiomalate or cyclophos­phamide. However, the lack of information re­garding the homogeneity of the treatment groups casts doubt on the validity of such comparisons.

In a I-year parallel study in 59 patients (Schorn, 1983) and a 3-year parallel study in up to 36 patients (Smith et aI., 1983), auranofin 6mg daily in single or divided doses was compared with D­penicillamine 750mg daily and sodium aurothio­malate 50mg weekly, respectively. Although both drugs produced similar improvement in hand function, auranofin therapy, unlike that of D-penicillamine, did not result in the reversal of the rheumatoid-associated osteoporotic process (Schorn, 1983). Smith et ai. (1983) noted that the rate of erosion was decreased by auranofin or sod­ium aurothiomalate only following 1 year of treat­ment with either agent, and that this effect was not

Table VIII, Summary of radiographic studies conducted to determine the effects of auranofin (A F) and other disease modifying agents (PL = placebo; DPN = D-peni­cillamine; ATM = sodium aurothiomalate) on the progression of rheumatoid-induced osteoporosis, joint narrowing, and erosive disease

Reference

Bandilla et aL (1982)

Gotton and 0' Brien (1983) [see also Gofton and O'Brien, 1982; Gofton et aI., 1983)

No. of patients (duration of study)

15 pts (12 months)

143 pts (12 and 24 months)

Homma et aL (1982) 37 pts (~ 12 weeks)

O'Brien (1981) 68 pts (18 months)

Weisman et aL (1982) 15 pts (4 years)

Dose of auranofin a

6 mg/day qd

Dose not specified

3mg bid

Study designb

Not

specified

1,2,4

6 mg/day (or less) 1, 2

3-9 mg/day (most patients on 4mg)

1,3

Assessment criteria

x-rays assessed by method of Larsenc

Rate of progression of erosive disease predicted by assessment of erosion prior to therapy (,placebo model'). Severity of erosive disease scored for each finger joint, individual carpel bone, radius, and ulna

Number of new erosions/patient/month determined from assessment of joints on paired hand films

'Placebo model' predicted as above (Gotton and O'Brien, 1983). Number and severity of erosions scored in every joint of hand and wrist

Clinical response graded as: - sustained improvement - initial, but unsustained improvement - no improvement. x-rays assessed by method of Larsenc

Significant findings/conclusions

Majority of films unchanged from pre-treatment. Progression of erosion occurred in some cases, and correlated well with clinical status of patient

Both readers found rate of progression of erosive disease to be less (p < 0.01) during AF therapy than that predicted by the 'placebo model'

Two readers determined an average 0.11 and 0.14 new erosions/patient/ month following an average 7.5-month treatment period

4,91 mean erosions/year predicted by 'placebo model' 0.66 mean erosions/year (p = 0.02) following 1 year AF therapy, and 0.5 mean erosions/year after 18 months

Three patients showed sustained improvement, 7 unsustained improvement, and 5 no improvement. No joint space narrowing occurred in any response group. Only 1 of 2 readers found a significant correlation between clinical response and change in erosive score

;I>

'" OJ :: o ~ ? ;I>

"0

:l 3' :;. ~

.:! ;Al r> <: (ii' :!;

+> o

Comparative studies

Larsen et al. (1983) 83 pts AF Doses not 3, 4 Modified method of Larsend Of pts treated with AF, 1M gold, or 73 pts '1M' gold specified PL, 57.8, 71.6 and 36.3% had no 11 pts PL progression in joint erosion, (1 year) respectively. Only 1M gold> PL (p

< 0.05). 48.2, 67.6, and 27.2% showed no worsening of mean joint grade, respectively. AF < 1M gold> PL (p < 0.025).

Schorn (1983) 17 pts AF AF 6 mg/day Ash weight of bone estimated by Metacarpal index increased (p < 42 pts DPN DPN 750 mg/day metacarpal index measurement from hand 0.0005) by DPN and decreased (p < (1 year) films. Hand function determined by ability to 0.025) by AF, indicating reversal of

perform daily activities demineralisation by DPN. Functional improvement DPN ;. AF

Smith et al. (1983) 16 pts AF AF 3mg bid 3 methods of scoring: AF (p < 0.01) and ATM (p < 0.004) [see also Smith et al. 20 pts ATM ATM 50mg - No. of bone defects/erosions and joint decreased rate of erosion 1982] (up to 72 weeks) weekly space narrowing (hand films only) development at 1 year only. No

- Right hand carpometacarpal ratio changes at 6, 18, or 27 months. measured (not all patients)" Joint space narrowing and - Method of Larsenc osteoporosis measurements were

unchanged by both drugs

a Or dose of agent compared to auranofin, where applicable. b 1 = x-ray films interpreted by 'blind' radiologist and read randomly as regards to sequence (pre- or post-treatment); 2 = reader blinded as to right or left hand nature

of film; 3 = retrospective; 4 = multicentre. c Method of Larsen = scoring system based on increasing erosion and joint space narrowing on hand and foot films. d Modification included removal of joint-space narrowing assessment and reduction of the number of total joints assessed. e The carpometacarpal ratio is calculated by dividing the lengths of the carpus by the third metacarpal and correlates highly with recognised radiographic stages of

rheumatoid arthritis (Trentham and Masi, 1976).

» c "1

'" ::s 0 ;::!l ::s .. » '"0 "1 2 3 :;. '" ,:;I ;.::I

'" -< ;;;. ~

+>

Auranofin: A Preliminary Review

persistent. Finally, in a placebo-controlled com­parison of auranofin and sodium aurothiomalate (Larsen et aI., 1983), only sodium aurothiomalate was found to significantly decrease the progression of joint erosion.

Recent studies have shown a lack of radiologi­cal progression of disease following I year's treat­ment with auranofin (Ciompi et aI., 1983; Tvede and Strandberg, 1983); however, these studies were uncontrolled and assessment criteria were not re­ported.

In view of the sometimes questionable assess­ment and comparative criteria, the large number of negative findings, and the sporadic nature of the positive findings, there appears to be insufficient evidence to conclude that auranofin has any effect on the occurrence or progression of osteoporosis, joint narrowing, or erosive processes associated with rheumatoid arthritis. Further well-designed trials are required to determine more clearly whether auranofin can decrease the severity or rate of pro­gression of the arthritic process.

3.2 Juvenile Rheumatoid Arthritis

The safety and preliminary efficacy of auranofin in the treatment of juvenile rheumatoid arthritis was evaluated in 21 patients (age 1.5 to 17 years) in an open-ended uncontrolled trial (Brewer et al., 1983; Giannini et aI., 1983a). Auranofin 0.1 to 0.2 mg/kg/day over an average treatment period of 12.1 months resulted in clinically significant improve­ment (> 25%) in half of the patients tested as meas­ured by decreases in number and severity of swol­len joints, pain on motion, and joint tenderness. Functional class was improved in 4 of the children, and II of 16 showed greater than 25% decreases in erythrocyte sedimentation rate. Therapy with auranofin was discontinued in I child due to inef­ficacy, and in 2 children because of side effects. Although efficacy data in uncontrolled trials must be cautiously interpreted, the response to aurano­fin demonstrated by these patients is promising. Double-blind controlled studies of auranofin in ad­equate numbers of patients with juvenile rheu­matoid arthritis are needed in order to further

412

clarify its potential role in the treatment of this dis­ease.

3.3 Other Areas of Use

In a 2-year pilot study of 13 patients with sys­temic lupus erythematosis (but without renal dis­ease) [Weisman et aI., 1983], auranofin 6mg daily induced significant improvement in physician's global assessment of disease severity (percent ana­logue scale, 0.37 to 0.26; p < 0.013), daily pred­nisone dose (8.38 to 5.7mg daily; p < 0.027), and serum haemolytic complement titration (64 to 80 units/ml; p < 0.001). However, other laboratory assessments and more objective clinical measure­ments of disease activity were not improved com­pared with baseline values.

Auranofin 6mg daily for i to 6 months was re­ported to have reversed the leucopenia and sple­nomegaly of 2 patients with Felty's syndrome (Tumiati et aI., 1983).

4. Side Effects

Auranofin has been well tolerated by most patients, but a number of troublesome and some­times serious side effects have been reported. In several instances, auranofin was implicated, but an absolute cause-effect relationship was not estab­lished. The nature of adverse effects with auranofin appears to be similar to that with parenteral gold compounds, but generally they are less severe with auranofin (section 3.1.4). Side effects influencing the lower gastrointestinal tract are the most com­mon problem with auranofin, whereas mucocutan­eous side effects have usually been most frequent with injectable gold compounds. To date, the with­drawal rate for adverse reactions has approximated 10% (Blodgett, 1983a,b). Wider clinical experience and monitoring of side effects are needed to estab­lish more clearly the long term effects of auranofin.

4.1 Gastrointestinal Effects

Gastrointestinal side effects occur frequently with auranofin, 42 to 58% of patients having ex-

Auranofin: A Preliminary Review

perienced some type of upper or lower gastroin­testinal disturbance (Ghozlan et aI., 1983; Heuer and Morris, 1983; Homma et aI., 1982; Katz et aI., 1982; Schattenkirchner et aI., 1982; Van Riel et aI., 1983a).

29 to 44% of patients on auranofin therapy have experienced loose stools or diarrhoea (Bandilla et aI., 1982; Heuer and Morris, 1983; Heuer et aI., 1983; Katz et aI., 1982; Schattenkirchner et aI., 1982; Van Riel et aI., 1983a), often accompanied by abdominal cramping (Baldassare et aI., 1980; Gottlieb et aI., 1980a; Van Riel et aI., 1983a). Diar­rhoea secondary to auranofin may occur at any time in the course of treatment, but most often occurs within the initial 2 to 3 months of administration (Heuer and Morris, 1983; Homma et aI., 1982; Schorn, 1982; Tvede and Strandberg, 1983; Van Riel et aI., 1983a). Patients prone to diarrhoea and cramping with auranofin usually experience these effects within the initial few hours after taking the drug, leaving the patient symptom-free for the re­mainder of the day (Van Riel et aI., 1983a). The incidence of diarrhoea appears to be related to the size of the dose, but not frequency of administra­tion (Bandilla et aI., 1982, 1983b; Hafstrom, 1983), and is apparently increased in patients of low bodyweight (Homma et al., 1982).

Diarrhoea secondary to auranofin has not been associated with weight loss (Hafstr6m, 1983), gas­trointestinal bleeding (Hafstrom, 1983; Van Riel et aI., I 983a), or malabsorption as determined by lac­tose tolerance, Schilling's test, or D-xylose testing (Bandilla et aI., 1982; Van Riel et aI., 1983a). Small bowel biopsy and proctoscopy in these patients have revealed no abnormalities (Bandilla et aI., 1982). The diarrhoeal stool is characterised by nor­mal osmolarity, and high sodium and low potas­sium content (Van Riel et aI., 1983a). Mild stea­torrhoea was present in 2 patients studied by Bandilla et ai. (1982), but Van Riel et ai. (1983a) reported normal faecal fat content in patients with auranofin-induced diarrhoea. The mean serum gold concentration in these patients was no different to that in patients with normal stools on the same dosage, suggesting that gold absorption is not af­fected by diarrhoea (Van Riel et aI., 1983a).

413

Auranofin-induced diarrhoea may be controlled by a reduction in dose (Bandilla et aI., 1982), use of variable dosage regimen (Smith et aI., 1982), ap­propriate symptomatic treatment (Bandilla et aI., 1982; Hafstrom 1983), increase in dietary fibre (Heuer and Morris, 1983), oral iron administration (Van Riel et aI., 1983a) or, if all else fails, drug withdrawal (Bandilla et aI., 1982). Diarrhoea may or may not recur when therapy is reinstituted after temporary withdrawal (BerglOf et aI., 1978).

Jarner and Nielsen (1983) reported 1 case of en­terocolitis which had occurred secondary to aur­anofin treatment (3mg twice daily; total dose I 68mg), characterised by abdominal pain, diar­rhoea (bloodless), high fever and dehydration. Rec­to scopic examination of the patient revealed an oedematous mucosa without ulceration, while ab­dominal radiographs showed an increasing dila­tation of the large bowel compatible with toxic megacolon. Recovery was complete following discontinuation of auranofin and treatment with total parenteral nutrition, corticosteroids, and anti­biotics. Gold-induced enterocolitis has also been reported with parenteral gold compounds (Fam et aI., 1980; Stein and Urowitz, 1976).

Although most side effects occur in the lower gastrointestinal tract, epigastric pain (Bandilla et aI., 1982; Calin et aI., 1982), erosive gastritis (Felix­Davies et aI., 1982, 1983) and nausea (Schorn, 1982) have occurred in association with auranofin treat­ment. Concomitantly administered non-steroidal anti-inflammatory drugs may have played an ac­tive role in some of these reactions (Heuer and Morris, 1983). Abnormalities in taste sensation have also been reported (Bandilla et aI., 1982; Homma et aI., 1982; Katz et aI., 1982).

4.2 Haematological Effects

Anaemia has been reported to occur occasion­ally either as a direct effect or secondary to aur­anofin-associated haematuria (Bernhard, 1982b; Giannini et aI., 1983a).

Auranofin has also been associated with a gen­eral leucopenia (Lewis et aI., 1982; Schorn, 1982; Williams, 1982), lymphopenia (Hunt and Holt,

Auranofin: A Preliminary Review

1981), neutropenia (Calin et aI., 1982; Hunt and Holt, 1981) and eosinophilia (Edelman et aI., 1983; Williams, 1982), which in I study (Edelman et aI., 1983) occurred in 13% of patients. Pre-existing eo­sinophilia is not a reliable indicator of potential auranofin gold toxicity (Edelman et aI., 1983).

Thrombocytopenia has been reported following auranofin administration (Bernhard, 1982b; Katz et aI., 1982; Schorn, 1982; Smith et aI., 1982), al­though it is uncommon « 0.5% of patients) [Heuer and Morris, 1983]. Once auranofin is withdrawn, platelet counts have returned to the normal range within I to 2 weeks (Bernhard, 1982b).

4.3 Renal Effects

Proteinuria has occurred in many clinical trials (Bandilla et aI., 1983b; Bernhard, 1982b; Ehrlich et aI., 1979; Giannini et aI., 1983a; Katz et aI., 1982; Menard et aI., 1982), but it has only rarely pro­gressed to the nephrotic syndrome (Plaza et aI., 1982; Revach et aI., 1979). A study of approxi­mately 600 patients receiving auranofin revealed the incidence of proteinuria to be no greater than 5% (Heuer and Morris, 1983), but the incidence was 13% in one multicentre study of 449 patients treated with auranofin 6mg daily in single or di­vided doses (Band ilia et aI., 1983b). In a patient with auranofin-induced nephrotic syndrome, per­cutaneous renal biopsy demonstrated electron-dense material in subepithelial areas of kidney basement membrane and IgG immunodeposits consistent with antigen-antibody complexes. These would suggest that auranofin-induced proteinuria is a hypersensitivity type of reaction. Gold was not found in the IgG immunodeposits, and the mech­anism by which gold compounds initiate deposi­tion of such complexes is unknown (Plaza et aI., 1982). Mild to moderate proteinuria can be de­creased, or stopped in some cases, by reduction of auranofin dosage (Giannini et aI., 1983a), but sev­ere proteinuria may require 4 to 6 months to com­pletely dissipate following auranofin withdrawal (Plaza et aI., 1982; Revach et a!., 1979).

Haematuria associated with auranofin has been reported in a few patients (Barraclough et a!., 1982;

414

Berglof et a!., 1978; Giannini et aI., 1983a; Schorn, 1982), generally following at least 2 to 3 months of therapy (Berglof et aI., 1978). Renal biopsy in I patient who developed 4 months of haematuria after 21 months of auranofin revealed modest focal and segmental mesangial hypercellularity (Schorn, 1982). However, it was unclear whether these changes were caused by auranofin or were due to the underlying rheumatic disease.

4.4 Mucocutaneous Effects

In 3 studies (Bandilla et aI., 1982; Ghozlan et aI., 1983; Homma et aI., 1982), mucocutaneous side effects occurred in 31 to 43% of patients treated with auranofin. These effects have usually been mild and have readily resolved following a reduc­tion in dosage or temporary withdrawal of auran­ofin (Smith et aI., 1982). Approximately 18 and 24% of patients treated with auranofin have developed skin rash or pruritus, respectively (Heuer and Mor­ris, 1983; Heuer et aI., 1983; Schattenkirchner et aI., 1982). Both conjunctivitis and stomatitis have been reported to occur in approximately 10% of patients treated with auranofin (Heuer and Morris, 1983; Heuer et a!., 1983; Schattenkirchner et aI., 1982). Although pruritus and stomatitis are more likely to occur early in treatment, conjunctivitis appears to occur at a steady rate regardless of treat­ment duration (Heuer and Morris, 1983).

In two studies, 7 to 8% of patients have devel­oped alopecia, particularly following prolonged administration of auranofin (Bandilla et aI., 1982; Schattenkirchner et aI., 1982). However, an ana­lysis of worldwide experience with auranofin in­dicated that the usual incidence of alopecia is much lower (approximately 2%) [unpublished data on file; Smith, Kline & French]. The severity of alopecia has been decreased by reduction of the daily dos­age (Bandilla et aI., 1982).

4.5 Other Reactions

Corneal and lens chrysiasis (which commonly occur during long term parenteral gold therapy) and skin chrysiasis (which occurs less frequently) have

Auranofin: A Preliminary Review

not been reported to occur following long term auranofin treatment (Blodgett, 1983b; Gott­lieb, 1982).

A few instances of severe recurrent headache (Giannini et aI., 1983a) and muscle pain (Schorn, 1982) have been reported during auranofin treat­ment, and Menard et al. (1982) reported I case of possible gold pneumonitis ('gold lung') associated with auranofin administration.

5. Dosage and Administration

In general, it is reasonable to consider the ini­tiation of chrysotherapy in patients with definite or classic rheumatoid arthritis which continues to be active or progressive despite adequate thera­peutic dosages of non-steroidal anti-inflammatory drugs, intra-articular injections of corticosteroids, rest and physiotherapy (Goldman and McDonald, 1983; Gottlieb, 1977; Sigler, 1983; Jessop, 1979; Kaplan, 1983; Katz, 1982; Lipsky, 1983).

In most patients, the recommended daily dos­age of auranofin is 6mg administered in single or divided doses and taken with meals. Although therapeutic response with auranofin has usually been observed within 3 months, some patients may require as long as 12 months to manifest an op­timum response (Heuer and Morris, 1983). If a re­sponse has not occurred within 4 to 6 months, an increase in dosage to 9mg daily is recommended. Patients on parenteral gold treatment may be transferred to oral therapy without the need for either an 'overlap' or 'washout' period (Berry et aI., 1983; Davis, 1983; Parke et aI., 1983; Wenger et aI., 1983b).

Auranofin is contraindicated in patients who have previously exhibited enterocolitis, pulmonary fibrosis, or exfoliative dermatitis due to injectable gold compounds. In addition, it is advised that auranofin not be administered to patients with progressive renal disease or severe active hepatic disease, or to patients with a history of bone mar­row toxicity. It is recommended that auranofin be used with caution in patients with a history of se­rious toxicity to parenteral gold compounds, In­

flammatory bowel disease, or atopy.

415

Usual precautions during auranofin treatment should include frequent inquiry regarding the oc­currence of gastrointestinal disturbance, pruritus, dermatitis, stomatitis, or conjunctivitis. Complete blood counts and urinalysis should be performed prior to therapy and at least monthly thereafter. Management of gold toxicity due to auranofin therapy is dependent upon the type and severity of the reaction. Reversal of most gastrointestinal and mucocutaneous side effects may be accomplished by temporary drug withdrawal and/or reduction in dose, whereas renal and haematological reactions, especially when severe, necessitate drug with­drawal.

6. The Place of Auranofin in Therapy

Therapeutic trials indicate that auranofin is an orally active and effective drug for the treatment of rheumatoid arthritis, although available com­parative reports suggest that auranofin may be somewhat less active than sodium aurothiomalate. Insufficient data are available to determine clearly the efficacy of auranofin relative to that of auro­thioglucose, D-penicillamine or antimalarial agents. Compared with most of these drugs, however, aur­anofin is well-tolerated, side effects being less sev­ere than with parenteral gold treatment and usually readily controlled by a decrease in dosage. Never­theless, as proteinuria and thrombocytopenia also occur with auranofin, routine laboratory testing is required.

The effect of auranofin on the radiologically de­tected progression of rheumatoid arthritis is un­clear, but present studies suggest that auranofin may be of particular use in patients with moderately ac­tive disease of recent onset which is poorly re­sponsive to non-steroidal anti-inflammatory agents and other conventional therapies, before the use of more toxic agents is considered. It has not yet been clearly established whether auranofin is safe and effective in patients who have had adverse reac­tions to parenteral gold compounds.

Thus, while additional well designed long term studies are needed to definitively define the place

Auranofin: A Preliminary Review

in therapy of auranofin in active rheumatoid arth­ritis, it is clear it offers a worthwhile addition to the small number of agents with disease-modifying potential.

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Auranofin: A Preliminary Review

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Author's address: Michael O. Chl1(fman, ADIS Drug Information Services. P.O. Box 34-030, Birkenhead, Auckland 10 (New Zealand).

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