Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial

A prospective controlled, double-blind multicenter trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombocytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, "nitritoid" reactions, and "gold pneumonitis" were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.     

Low-dose D-penicillamine therapy in rheumatoid arthritis. A controlled, double-blind clinical trial

Two hundred twenty-five patients with active severe rheumatoid arthritis were admitted to a multiclinic, controlled, double-blind trial comparing the use of 500 mg D-penicillamine per day, 125 mg D-penicillamine per day, and placebo. One hundred seventy-one patients completed at least 30 weeks of therapy. The 500 mg D-penicillamine group demonstrated statistically significant improvement over the placebo group in grip strength, average circumference of swollen proximal interphalangeal joints, and patient assessment. While the trend was for greater improvement with the larger dose of D-penicillamine, there was no statistically significant difference among the 3 groups in duration of morning stiffness, walking time, physician's assessment, number of swollen joints, or scores for tender and swollen joints. The slight increase in efficacy of higher dose D-penicillamine was associated with increased toxicity.     

Low-Dose D-Penicillamine Therapy in Rheumatoid Arthritis

Two hundred twenty-five patients with active severe rheumatoid arthritis were admitted to a multiclinic, controlled, double-blind trial comparing the use of 500 mg D-penicillamine per day, 125 mg D-penicillamine per day, and placebo. One hundred seventy-one patients completed at least 30 weeks of therapy. The 500 mg D-penicillamine group demonstrated statistically significant improvement over the placebo group in grip strength, average circumference of swollen proximal interphalangeal joints, and patient assessment. While the trend was for greater improvement with the larger dose of D-penicillamine, there was no statistically significant difference among the 3 groups in duration of morning stiffness, walking time, physician's assessment, number of swollen joints, or scores for tender and swollen joints. The slight increase in efficacy of higher dose D-penicillamine was associated with increased toxicity.     

Comparison of auranofin,gold sodium thiomalate,and placebo in the treatment of rheumatoid arthritis

A prospective controlled, double-blind multi-center trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombo-cytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, “nitritoid” reactions, and “gold pneumonitis” were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.     

Auranofin (SK&F) in early rheumatoid arthritis: results from a 24-month double-blind, placebo-controlled study. Effect on clinical and biochemical assessments

In a 2-year, randomized, double-blind Nordic multicentre trial, auranofin was compared with placebo in early (disease duration less than or equal to 2 years), active rheumatoid arthritis (RA). Efficacy and safety were analysed in 67 patients receiving auranofin and 65 receiving placebo. Life table analysis demonstrated a significantly higher withdrawal rate due to insufficient therapeutic effect in the placebo group, whereas more patients dropped out due to side effects in the auranofin group. More auranofin than placebo patients (35 vs. 24) completed the 2 years. Clinical and inflammatory activity improved in both groups, but consistently more so in the auranofin group, in spite of the greater consumption of local steroids and NSAIDs in the placebo group. The most frequent side effects leading to withdrawal in the auranofin group were cutaneous and gastrointestinal reactions. The study demonstrated that most patients exhibit improvement in clinical signs and symptoms and about half of all patients with early RA continue to take auranofin for at least 2 years.     

Auranofin versus penicillamine in rheumatoid arthritis. One-year results from a prospective clinical investigation

Forty patients with definite or classical active rheumatoid arthritis were stratified by the minimization procedure to auranofin (6 mg/day) or penicillamine (go slow and low regime). This investigation is a prospective planned 3 year patient and 'doctor-open' as well as 'doctor-blind' clinical trial. This article describes the results after 12 months. Both drugs decreased disease activity and improved the functional capacity in a similar way. Two patients in the auranofin group and 5 in the penicillamine group stopped treatment due to major side effects. Four other patients in the auranofin group left treatment: 2 due to death from unrelated cause and 2 according to the Helsinki II Declaration. After one year a further patient in the auranofin group and 2 in the penicillamine group stopped treatment due to lack of clinical effect. Side effects due to auranofin were statistically more frequent distal in the gastrointestinal tract (loose stools/diarrhoea) than with penicillamine. In contrast, penicillamine produced significantly more side effects in the oral cavity (mainly taste disturbances) than auranofin. Other side effects were about equal in the two groups, but 2 cases of severe proteinuria and one with obstructive lung disease were observed in the penicillamine group. Only 3 patients did not complain of any untoward effect during the 12-month period. We conclude that on the basis of this one year investigation it is an open question whether one should select auranofin or penicillamine for the treatment of clinical active rheumatoid arthritis.     

Auranofin in the treatment of juvenile rheumatoid arthritis

A 6-month double-blind, parallel, randomized, placebo-controlled multicenter trial of auranofin (0.15–0.20 mg/kg/day) was conducted in 231 children with juvenile rheumatoid arthritis (JRA) in the United States and in the Union of Soviet Socialist Republics. Approximately 80% of the children had polyarticular disease. The auranofin-treated patients showed greater mean decreases from baseline in 11 of the 12 articular disease indices measured than did the placebo-treated subjects after 3 months of therapy, and in 9 of the 12 indices after 6 months. However, the actual intergroup mean differences were relatively small and were not statistically significant. According to the physician's global assessment, 69% of the auranofin-treated patients and 61% of the placebo-treated patients demonstrated clinically significant improvement from baseline after 6 months (P = 0.24). Children whose disease onset occurred less than 2 years prior to entry improved more than did those who had arthritis for a longer period. In addition, those with polyarticular involvement at baseline improved more than did patients with mild disease. However, these relationships were observed in both the auranofin- and placebo-treated groups, and again, there were no significant intergroup differences. Diarrhea was the most common adverse effect of auranofin. We conclude that the clinical efficacy of auranofin is modestly higher than that of placebo in the treatment of JRA, as evidenced by the consistent trends observed in the data. However, the magnitude of the individual intergroup differences is not statistically significant. Auranofin appears to be very safe in children with JRA.     

Auranofin in the treatment of juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The USA Pediatric Rheumatology Collaborative Study Group. The USSR Cooperative Children's Study Group

A 6-month double-blind, parallel, randomized, placebo-controlled multicenter trial of auranofin (0.15-0.20 mg/kg/day) was conducted in 231 children with juvenile rheumatoid arthritis (JRA) in the United States and in the Union of Soviet Socialist Republics. Approximately 80% of the children had polyarticular disease. The auranofin-treated patients showed greater mean decreases from baseline in 11 of the 12 articular disease indices measured than did the placebo-treated subjects after 3 months of therapy, and in 9 of the 12 indices after 6 months. However, the actual intergroup mean differences were relatively small and were not statistically significant. According to the physician's global assessment, 69% of the auranofin-treated patients and 61% of the placebo-treated patients demonstrated clinically significant improvement from baseline after 6 months (P = 0.24). Children whose disease onset occurred less than 2 years prior to entry improved more than did those who had arthritis for a longer period. In addition, those with polyarticular involvement at baseline improved more than did patients with mild disease. However, these relationships were observed in both the auranofin- and placebo-treated groups, and again, there were no significant intergroup differences. Diarrhea was the most common adverse effect of auranofin. We conclude that the clinical efficacy of auranofin is modestly higher than that of placebo in the treatment of JRA, as evidenced by the consistent trends observed in the data. However, the magnitude of the individual intergroup differences is not statistically significant. Auranofin appears to be very safe in children with JRA.     

A double-blind placebo-controlled study of auranofin in patients with psoriatic arthritis

Two hundred thirty-eight patients with psoriatic arthritis were entered into a 6-month, multicenter, double-blind trial comparing auranofin and placebo. Polyarthritis (greater than 5 tender joints) was present in 90% of the patients, and 94% were seronegative. Auranofin treatment was statistically superior to placebo treatment, according to physician's global assessment and functional scores. A trend in favor of auranofin treatment was seen for each of the other disease parameters studied. Psoriasis worsened in 6 auranofin-treated patients and in 3 placebo-treated patients. The incidence and nature of other side effects were similar to those observed in similar trials of patients with rheumatoid arthritis. Our observations suggest that the use of auranofin in the treatment of psoriatic arthritis is safe, although its therapeutic advantage over treatment with nonsteroidal antiinflammatory drugs alone is modest.     

Reversible nephrotoxicity of cyclosporine in rheumatoid arthritis

Irreversible nephrotoxicity has limited the use of cyclosporine in rheumatoid arthritis (RA). In a randomized clinical trial we compared 26 weeks of cyclosporine (5 mg/kg) and D-penicillamine (250 mg) treatment in 92 patients with RA with a serum creatinine less than 100 mumol/l. We adjusted the starting dose according to clinical response and side effects. During cyclosporine treatment the serum creatinine increased by median 15% (p less than 0.0001 vs baseline), quickly reversible after stopping (median followup: 1.6 years). Six patients stopped cyclosporine prematurely because of nephrotoxicity. In the D-penicillamine group the values remained at baseline.     

SA 96 (N-(2-mercapto-2-methylpropanoyl)-L-cysteine) in rheumatoid arthritis

SA 96 (N-(2-mercapto-2-methylpropanoyl)-L-cysteine) is a new sulfhydryl compound having a relatively similar chemical structure to Tiopronin and D-penicillamine. An open trial of SA 96 treatment (300 mg/day after meals for 16 weeks) was carried out in 11 patients with definite or classical rheumatoid arthritis and with therapeutic failure of previous gold salts and/or D-penicillamine therapy. Two cases were withdrawn from the trial, because of a side effect (hepatitis) in one patient and an unrelated illness in another. The results in the 9 patients completing the trial demonstrated statistically significant improvement in the clinical and laboratory measurements. A marked abatement of disease activity was noted in 5 of 9 patients who did not benefit from, or suffered a relapse during previous chrysotherapy and in 1 of 5 patients without benefit, or with relapse following previous D-penicillamine treatment. Among 4 patients who had discontinued D-penicillamine because of its intolerable cutaneous side effects, 3 patients completed the trial, with favourable results. The results of this trial seem to indicate that SA 96 is possibly of value as a slow-acting antirheumatic drug in some patients with therapeutic failure of gold salts or D-penicillamine.     

Prospective trial comparing the use of sulphasalazine and auranofin as second line drugs in patients with rheumatoid arthritis.

Two hundred patients with rheumatoid arthritis were studied in a prospective open trial comparing treatment with sulphasalazine and auranofin in patients with active disease over 12 months. The two drugs improved many parameters of disease activity at 12, 24, and 48 weeks. At 12 weeks, the group treated with sulphasalazine had a lower platelet count (Mann-Whitney U test), erythrocyte sedimentation rate, and articular index, with a greater decrease in erythrocyte sedimentation rate (Students t test) and C reactive protein between 0 and 12 weeks. There were no significant differences between sulphasalazine and auranofin treatment after 24 and 48 weeks. Life table analysis showed no significant differences in the rate of side effects which caused treatment to be stopped. Sulphasalazine works more rapidly, may be a more effective disease modifying antirheumatic drug, and is as well tolerated as auranofin.     

Comparison of cyclosporine and D-penicillamine for rheumatoid arthritis: a randomized, double blind, multicenter study

Ninety-two patients with active rheumatoid arthritis (RA) were entered in a randomized double blind study of 24 weeks comparing cyclosporine (initial daily dose 5 mg/kg) with D-penicillamine (initial daily dose 250 mg). The groups were well balanced in baseline characteristics. In the cyclosporine group, 10 patients stopped prematurely, one because of inefficacy. In the D-penicillamine group, 9 patients stopped prematurely, 3 because of inefficacy. The 2 antirheumatic drugs were equally effective in reducing disease activity, except for a significant (p = 0.005) decrease in erythrocyte sedimentation rate with D-penicillamine treatment. We conclude that under the conditions of this trial, cyclosporine can serve as an alternative to D-penicillamine for the treatment of patients with RA.     

Effects of piroxicam and D-penicillamine on T lymphocyte subpopulations, natural killer cells and rheumatoid factor production in rheumatoid arthritis

The effects of piroxicam and D-penicillamine on T lymphocytes, NK cell activity and rheumatoid factor production as well as clinical parameters were studied in patients with rheumatoid arthritis. The level of total rheumatoid factor fell during treatment with D-penicillamine (p less than 0.02) and there was a positive correlation (K greater than 0.50, p less than 0.05) between this fall in rheumatoid factor and the improvement of several clinical activity parameters. No significant change was observed in the level of rheumatoid factor during treatment with piroxicam. Natural killer cell activity decreased from 21.1 +/- 2.5 to 15.8 +/- 1.9 after treatment with piroxicam for 3 weeks (p less than 0.05) as compared with changes in the controls. No change in natural killer cell activity was seen after treatment with D-penicillamine. Moreover, no significant changes in the numbers of T4+ and T8+ lymphocytes nor in the numbers of HLA-DR positive T cells were seen in the two treatment groups. Both laboratory and clinical activity parameters improved during the treatment with D-penicillamine, while only subjective parameters improved during treatment with piroxicam.     

Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial.

We conducted a double-blind, randomized trial comparing azathioprine (AZA) and methotrexate (MTX) in the treatment of patients with rheumatoid arthritis in whom parenteral gold and/or D-penicillamine treatment had been unsuccessful. Patients were randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly). After 8 weeks, the dosage was increased depending on the clinical improvement. Sixty-four patients were followed up for 48 weeks (33 AZA, 31 MTX). Comparison of values at week 24 with baseline values revealed significant improvement in 12 of 13 disease variables in the MTX group and in 6 of 13 in the AZA group. Comparison between the 2 treatment groups at 24 weeks, by area-under-the-curve analysis, showed significantly more improvement in the MTX group in terms of the swollen joint count, pain score, erythrocyte sedimentation rate, C-reactive protein level, hemoglobin level, thrombocyte level, and disease activity score. A significant overall clinical improvement (disease activity score) was found in 7 of 20 patients treated with AZA and 18 of 30 patients treated with MTX after 24 weeks of therapy, and in 6 of 12 AZA-treated patients and 19 of 25 MTX-treated patients after 48 weeks. The number of withdrawals due to side effects was significantly higher in the AZA group. After 48 weeks, only 12 patients from the AZA group (36%), but 25 from the MTX group (81%), were still using the initial drug. These results demonstrate MTX to be superior to AZA in the treatment of rheumatoid arthritis, with a more rapid clinical improvement which is sustained after 1 year, accompanied by a lower rate of serious adverse reactions.     

Clinical effectiveness and tolerance of auranofin in patients with chronic polyarthritis. Results of a multicenter long-term study

In an open multicenter trial, 90 patients with rheumatoid arthritis were treated with a daily dose of 6 mg auranofin. The duration of the treatment was 12 months. A significant improvement in the following parameters was observed: grip strength, number of swollen and painful joints after the 4th month, blood erythrocyte sedimentation rate decreased significantly after the 2nd month. Of the 90 patients, 56 (62.3%) completed the therapy, in 14 (15.5%) it was discontinued because of side effects and in 8 (8.9%) because of inefficacy. 12 patients (13.3%) stated other reasons for discontinuing the therapy (non compliance). The reported side-effects were mostly gastrointestinal, especially diarrhoea and loose stools. The evaluation of results referring to the duration of the disease shows that patients with a duration of less than 2 years reacted better to the improvement with auranofin therapy than patients with a longer sickness history.     

Auranofin and D-penicillamine: a one year comparative study of safety and efficacy in patients with rheumatoid arthritis followed by a two year open assessment of auranofin

Clinical Rheumatology - Forty-six patients with classical or definite rheumatoid arthritis participated in a prospective clinical trial comparing auranofin 6 mg/day (26 patients) with...     

Lack of induction of antinuclear antibodies by D-penicillamine in rheumatoid arthritis: a controlled study

The induction of antinuclear antibodies (ANA) by D-penicillamine (DP) was studied in 148 patients with rheumatoid arthritis (RA) who had completed at least 30 weeks in a double blind trial which compared DP at doses 500 mg and 125 mg daily to placebo. There was no difference among the 3 groups in the frequency of a positive ANA at any titer or at a titer greater than 1:16 either pretreatment or at the end of the study. The conversion from a negative to a positive ANA occurred as frequently in the placebo treated controls with RA as in the DP treated RA patients. Antibodies to native DNA appeared in 3 DP treated patients, none of whom had symptoms of drug induced lupus or of DP toxicity.     

Changes in therapy of rheumatoid arthritis during the period 1979 to 1996

OBJECTIVE: To evaluate the use of disease modifying antirheumatic drugs (DMARDs), cytotoxic agents, and corticosteroid therapy in patients diagnosed with rheumatoid arthritis (RA) in two periods, 1979 to 1987, and 1988 to 1996. MATERIALS AND METHODS: Review of the records of 788 patients with RA diagnosed at the Department of Rheumatology, the University Hospital of Troms?. RESULTS: We found a significant increase in the proportion of patients who started with auranofin, sulfasalazine, methotrexate, and corticosteroids in 1988 1996 compared to 1979 1987. The initiation of use of gold salts, antimalarials, and D-penicillamine declined significantly from the first to the second period. CONCLUSION: Patients diagnosed with RA between 1988-1996 were treated more actively than patients diagnosed in the period 1979-1987. During 1988 to 1996 auranofin, sulphasalazine, methotrexate, and corticosteroids replaced gold salts, antimalarials, and D-penicillamine.     

The toxicity of D-penicillamine in systemic sclerosis

We studied D-penicillamine toxicity in 259 patients with systemic sclerosis treated since 1972. The average daily dose of 635 mg was given for a mean of 1.8 years. Of patients with systemic sclerosis, 47% has side effects from D-penicillamine treatment, similar to the 56% of 807 patients with rheumatoid arthritis in seven separate series. Individual manifestations of toxicity included rash, proteinuria, gastrointestinal symptoms, dysgeusia, oral ulcers, thrombocytopenia, and neutropenia. Four episodes each of myasthenia gravis and pemphigus occurred in our patients; both were reported rarely in patients with rheumatoid arthritis. Adverse effects occurred more frequently after rapid increases in dosage. Treatment had to be discontinued due to toxicity in 29% of patients with systemic sclerosis and in 33% of those with rheumatoid arthritis. Although toxic, with a high frequency of adverse effects, D-penicillamine can be used safely in the treatment of systemic sclerosis. Pemphigus and myasthenia gravis may occur more frequently with therapy for systemic sclerosis than with that for rheumatoid arthritis.