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.     

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.     

Association of immunomodulators and HLA antigens in rheumatoid arthritis

We studied the association between HLA antigens and clinical response to immunomodulators or the toxic effects of immunomodulators in 191 patients with rheumatoid arthritis (RA). All patients received nonsteroidal anti-inflammatory drugs. Fifty-seven patients were treated with auranofin, 61 patients with penicillamine and 45 patients with lobenzarit. We found that HLA-Cw 1 is significantly (p less than 0.05) associated with a substantial clinical response to auranofin in RA patients (65% vs 33% of Cw 1-negative patients). We observed that HLA-DR 4 is a risk factor for the occurrence of toxic reactions to penicillamine (45% vs 21% of DR 4-negative patients: p less than 0.05) and that HLA-DRw 9 is a risk factor in the case of lobenzarit (62% vs 32% of DRw 9-negative patients: p less than 0.05). HLA-A 24-positive patients with RA experienced a low frequency of side effects from auranofin (16% vs 37% of A 24-negative patients: p less than 0.05). HLA-A 2 or Cw 7-positive patients with RA experienced a low frequency of side effects from penicillamine (12% vs 49% of A 2-negative patients: p less than 0.01, 17% vs 46% of Cw 7-negative patients: p less than 0.05). Our data demonstrated that HLA antigens are significantly associated with a clinical response to immunomodulators and the toxic effects of immunomodulators in patients with RA.     

Treatment of psoriatic arthritis with auranofin and gold sodium thiomalate

Summary Forty-two patients with psoriatic arthritis were included in a multicenter, double-blind trial comparing auranofin and gold sodium thiomalate (GST) for 6 months, followed by a 6-month open treatment. Fifty-two percent of the patients on auranofin and 33% on GST were able to complete the 1-year course of therapy. As a result of the study we conclude that both gold compounds are effective agents in the treatment of psoriatic arthritis. Degree of improvement of arthritis was better in the GST group, but the number of improved patients was greater in the auranofin group. Two patients on auranofin were withdrawn for side effects (one diarrhoea, one worsening of psoriasis) and 5 on GST (rash 2, total loss of appetite 1, exacerbation of psoriasis 2). Comparing the side effects of both compounds, auranofin is less likely to aggravate the psoriatic condition or result in withdrawal of patients for adverse reactions.     

5-thiopyridoxine in rheumatoid arthritis: clinical and experimental studies

Twelve patients with rheumatoid arthritis who had failed to respond to or developed side effects preventing further use of penicillamine were given 5-thiopy-ridoxine (5-TP). These patients were compared with 48 patients with similar indications randomly assigned to placebo or penicillamine. Both 5-TP and penicillamine were superior to placebo, and the effectiveness of the two active drugs was similar. Both produced a gradual amelioration of symptoms and signs of the disease accompanied by reduction in erythrocyte sedimentation rate, rheumatoid factor titer, and immunoglobulins. Nine patients on 5-TP were able to continue treatment with good control of the disease for at least 18 months. Toxic effects included rashes, proteinuria, loss of taste, and mouth ulcers. Patients who had developed a particular side effect with penicillamine did not necessarily do the same with 5-TP. This is the second mercaptan compound which has suppressive effects on the clinical and laboratory features of rheumatoid arthritis. Because of their similarities, 5-TP and penicillamine were studied in various experimental systems in an attempt to find some common biochemical or pharmacologic action. Among the properties studied were the effects on copper, vitamin B₆ metabolism, dermal collagen, and mixed disulfide formation. Results with animal models of inflammation were also examined. The only common action was enhancement of the secondary lesions of adjuvant arthritis.     

Second line (disease modifying) treatment in rheumatoid arthritis: which drug for which patient?

OBJECTIVES--The objectives were to assess (a) the comparative merits of commonly used disease modifying drugs in the treatment of rheumatoid arthritis (RA) and (b) the influence of age, gender, and disease duration on the outcome of treatment. METHODS--Collected analysis (meta-analysis) was performed on results obtained during the first year of treatment in 1140 patients with RA treated with gold, penicillamine, sulphasalazine, or auranofin from a single centre. RESULTS--Gold, penicillamine, and sulphasalazine performed similarly, with about 60% of patients continuing to receive each of these drugs for at least one year. Neither gender nor age had an influence on the response to treatment, but patients with a longer disease duration showed a greater tendency to stop treatment. The median percentage improvement was 33% in visual analogue pain score and 50% in erythrocyte sedimentation rate. CONCLUSIONS--Routine use of these drugs should at least equal these results. Any new drug should either be substantially less toxic or at least as efficacious.     

Auranofin or D-penicillamine in the treatment of rheumatoid arthritis

Ninety patients were entered into a randomized, controlled, double-blind trial lasting 12 months to compare auranofin (6 mg/d), and D-penicillamine (250 mg/d for 4 weeks, 500 mg/d for 4 weeks, then 750 mg/d thereafter) in the treatment of rheumatoid arthritis. Most patients in both groups completed the trial with significant improvement in all quantitative measures of efficacy. Patients treated with D-penicillamine were more likely to have "important improvement" in physician global assessment, swollen joint count, and score and grip strength. The overall frequency of side effects was similar between the two groups; however, more patients were withdrawn for adverse effects from the D-penicillamine group, and proteinuria (greater than or equal to 2+) and thrombocytopenia (less than 100 000 mm3) occurred significantly more frequently with D-penicillamine than auranofin (p = 0.028). These results suggest that in the dosage regimen used, auranofin is safer than D-penicillamine but that D-penicillamine tends to show greater clinical effectiveness in patients with rheumatoid arthritis.     

The use of penicillamine in the treatment of rheumatoid arthritis and scleroderma.

The use of penicillamine in the treatment of rheumatoid arthritis and scheroderma is reviewed. Much of the worlds literature was collected including both open studies and control studies. Both types with over 1,300 patients in the open trials and as one would expect, a smaller group in the control trials, showed about 64 percent of the patients having good results. Side effects range from one quarter to one third of the treated patients. This seems to show penicillamine as an effective drug for the treatment of rheumatoid arthritis though with a multiplicity of side effects. Its use in the treatment of scleroderma is still uncertain. Because of the rarity of the disease the number of patients treated has been small and the data is conflicting.     

A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis. Clinical benefits and skeletal side effects

OBJECTIVES: To study benefits and skeletal side effects of carefully monitored prednisolone treatment in patients with active rheumatoid arthritis. METHODS: One hundred and two patients with active rheumatoid arthritis were randomly allocated to treatment with disease modifying anti-inflammatory drug (DMARD) alone or DMARD and prednisolone in a one year follow up study. Prednisolone was given in a dose regimen adapted to the disease activity of the individual patient. The mean dose was 6 mg and the mean cumulated dose was 2160 mg. Patients were followed up with disease activity parameters, radiograph of the hands (Larsen score), and bone mineral density (BMD) of the lumbar spine, distal forearm and hand. At one year 26 patients had withdrawn from the investigation leaving 76 patients for evaluation. RESULTS: The results showed that disease activity in the prednisolone treated group was reduced within two weeks. In the DMARD alone group disease activity was gradually reduced over months. At six months there was no difference between the groups as evaluated by an improvement score using a number of ACR criteria. Prednisolone in the present set up was not able to protect significantly against radiological disease progression, although there was a trend towards less progression in Larsen score in the prednisolone group, a matter that was further underlined in an intention to treat analysis. BMD data revealed a significant reduction in spinal BMD in the prednisolone group, whereas prednisolone seemed to have a protective effect against bone loss in the hand and distal forearm. CONCLUSIONS: This study does not allow any firm conclusions for or against the treatment of rheumatoid arthritis with prednisolone. The data suggest that the beneficial effects of prednisolone are not as clear cut in established rheumatoid arthritis as in early disease. Furthermore the data indicate that treatment in the chosen relatively low dose does not provide sufficient control of disease. On the other hand the spinal bone loss observed in the prednisolone group does invite considerations about using higher doses.     

Some characteristics of RA patients with and without side effects due to gold treatment.

Gold treatment was initiated in 98 patients suffering from early-stage rheumatoid arthritis. In 30 patients side effects due to gold therapy were seen during the first follow-up year: proteinuria in 6, allergic symptoms in 23, and thrombocytopaenia in one patient. The serum IgM level was higher in patients with side effects. None of the 33 other parameters studied showed any significant differences between patients with or without side effects.     

A COMPARISON OF LOW DOSE LEVAMISOLE and PENICILLAMINE IN RHEUMATOID ARTHRITIS

Levamisole (150 mg once weekly) was compared with penicillamine (250 mg daily) in a single blind independent observer study in 28 patients with rheumatoid arthritis over twelve months. Fifty percent (8/16) of patients stopped levamisole, five within three months of starting, while only two of twelve stopped penicillamine. In those patients able to tolerate treatment for twelve months, both regimes produced a significant and comparable reduction in disease activity, with the onset of action of penicillamine occurring at three months compared with six to nine months for levamisole. Radiological progression of disease occurred in both groups. Levamisole in low dose may improve parameters of disease activity in rheumatoid arthritis but poor patient tolerance, slow onset of action and failure to prevent radiological progression limit its usefulness. (Aust NZ J Med 1983; 13: 578–582.)     

Clinical Trial of Penicillamine in Rheumatoid Arthritis

The medical records of our first 200 consecutive rheumatoid arthritis patients treated with penicillamine were analyzed retrospectively. All but 5 patients (97.5%) had undergone earlier chrysotherapy that resulted in either therapeutic failure or toxicity. Only 57 patients (28.5%) were still receiving penicillamine on January 1, 1981, and the duration of therapy ranged from 23 to 62 months. The dropout rate due to toxicity, therapeutic failure, relapse, or other reasons was very high (71.5%). Toxic effects required permanent discontinuance in 56 patients (28%). Therapy was discontinued for 36 patients (18%) because of no benefit. A striking number (20) had relapse after therapeutic success and while continuing to take penicillamine, and the therapy had to be discontinued, a relapse rate of 10%. Therapy for the remaining 15.5% was discontinued for miscellaneous reasons that were not related to penicillamine per se: patient anxiety (6%), lost to followup (5%), hospitalization for reasons unrelated to penicillamine therapy (2%), lack of cooperation and study protocol (1% each), or pregnancy (0.5%). By our criteria, 142 patients (71%) received benefit (remission or improvement). Therapy results for these patients were as follows: still on penicillamine on January 1, 1981 (28.5%); no longer receiving the drug due to toxicity (19.5%); no longer receiving penicillamine due to relapse while on continuing therapy (10%); no longer receiving penicillamine due to miscellaneous reasons not related to penicillamine therapy (13%). This study shows that penicillamine is a valuable drug in the treatment of rheumatoid arthritis, but its value in clinical practice is limited by a rather high incidence of both toxicity and relapse during treatment.     

Minimal changes nephrotic syndrome associated to penicillamine treatment

We describe three patients with minimal change nephrotic syndrome associated with penicillamine treatment. Two patients had systemic sclerosis and one had rheumatoid arthritis. Cumulative dose of D-penicillamine was similar in all cases, and nephrotic syndrome appeared after 15-33 months of treatment. The drug was stopped and nephrotic syndrome disappeared in 2-4 months, suggesting a possible causal relationship between penicillamine and minimal change disease.     

The long term effects of sulphasalazine in the treatment of rheumatoid arthritis and a comparative study with penicillamine

Summary The long term efficacy and tolerability of sulphasalazine (SASP) in the treatment of 21 patients with active classical or definite rheumatoid arthritis (RA) were examined and compared with the effects of penicillamine in a similarly active group of RA patients. Nineteen of the 21 patients treated with SASP improved during the first 6 months as shown by significant changes in the clinical and laboratory variables. Clinical improvement was maintained for the remainder of the year. Improvement in laboratory variables was maintained at 9 months but showed some deterioration at 1 year. Six patients went into remission by the ARA criteria, and 16 were able to continue the drug at the end of 1 year. In addition SASP had a steroidsparing effect in 4 of the patients on systemic steroids. No potentially dangerous side effects were encountered by the end of the first year, although 5 patients were withdrawn. Dyspepsia, nausea and abdominal discomfort were the most common side-effects, although rashes (3) and macrocytosis (2) also occurred. Eighteen of the 21 patients treated with penicillamine improved during 9 months,although there was some deterioration at 1 year. Eight patients were withdrawn because of side-effects — thrombocytopenia (5), nephrotic syndrome (1) and proteinuria(2). This study suggests that SASP has a disease modifying action maintained over a year and associated with low toxicity. It is a useful addition to the small number of second-line drugs with a possibly different mode of action.     

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.     

The glomerular filtration rate during penicillamine therapy in rheumatoid arthritis

Twenty-one consecutive patients (14 women and 7 men aged 35-68 years, mean age 50 years) with chronic active RNA for 2-24 years (mean 12.7 years) had a normal glomerular filtration rate (GFR) (mean value 99.8 +/- 14.8% (S.D.) of sex- and age-dependent normal value) before penicillamine treatment. All patients had previously been undergoing gold treatment; no patient had signs of renal disorder, or diabetes. GFR (total 51Cr-EDTA plasma clearance) was measured before and after 3 and 6 months' penicillamine treatment, respectively. Treatment was stopped because of side effects in 4 patients, including one with renal side effects. In the remaining 17 patients there was a mean fall in GFR of 3.8 +/- 12.5 (S.D.) ml/min during 6 months' penicillamine treatment, which was not significant. There was no correlation between individual changes in GFR and penicillamine dose. The individual changes in GFR correlated well to individual changes in plasma creatinine. Repeated determinations of plasma creatinine should be done during penicillamine treatment.     

Penicillamine-induced dermatomyositis. A case history

A 69-year-old woman with classical rheumatoid arthritis developed a severe dermato-myopathy during treatment with penicillamine. Remission occurred on withdrawal of the drug. Penicillamine (dimethylcysteine) is a pharmacological agent used for its chelating properties in the treatment of Wilson's disease and heavy metal poisoning, and in cysteinuria because of soluble disulphide formation. Within the last 17 years penicillamine has been increasingly applied in the treatment of rheumatoid arthritis, the mechanism of action still being unknown. A great number of side effects have been reported, including less common auto-immune disorders such as drug-induced systemic lupus erythematosus, myasthenia gravis and polymyositis. These and other possible side effects have been well reviewed by others (1, 2). To our knowledge only a few earlier cases of dermatomyositis as a complication to penicillamine treatment of rheumatoid arthritis have been reported (3, 4, 5). We describe here another case.     

Effect of oral gold salt therapy on bile acid absorption in rheumatoid arthritis patients

Summary Several studies pointed out an altered stool pattern as the most common side effect of auranofin therapy. The major mechanism in the aetiology of auranofin-induced impairment in bowel habit seems to be the inhibition of Na⁺/K⁺ A TPase in the gut. In vitro experiments proved that auranofin can affect active bile acid (BA) reabsorption in rat terminal ileum; this action, due to the ability of the drug to reduce Na⁺ pump activity by inhibiting Na⁺/K⁺ATPase, may make a significant contribution to the auranofininduced diarrhoea. The ability of auranof in to reduce the Na⁺ gradient necessary for active BA reabsorption, however, could cause a decrease of serum BA levels in patients taking auranofin before or without the development of an overt diarrhoea. We measured fasting and postprandial serum conjugated BA levels in 10 female rheumatoid arthritis patients before and after one month and two months' auranofin treatment. No patient developed diarrhoea during the chrysotherapy. When oral gold salt therapy was started, we observed a slight decrease in serum BA levels, but difference was not statistically significant. We can conclude that auranofin therapy does not cause BA malabsorption in patients who do not develop diarrhoea during the treatment.     

Penicillamine-induced myositis. Observations and unique features in two patients and review of the literature

Dermatomyositis developed during treatment with penicillamine in two patients with rheumatoid arthritis. Both were male without a history of penicillin allergy. Eosinophilia was present at the start of their illness, and HLA tissue typing showed the presence of HLA-DR2 in one patient. One patient was retreated with penicillamine and remained asymptomatic after three years of therapy, and the other was able to take penicillamine in a reduced dosage.     

Humanized monoclonal antibody treatment in rheumatoid arthritis.

A 41-year-old woman with active, seropositive erosive rheumatoid arthritis was treated with the humanized monoclonal antibody Campath 1H. She had not responded or developed side effects to myocrisin, sulfasalazine and penicillamine, and had not responded to inpatient bedrest and physiotherapy. There was a rapid clinical improvement within 24 hours of infusion, which was maintained for about 12-14 weeks after the infusion. The lymphocyte count was suppressed for 7 months after treatment. There were no significant side effects during or after treatment. No anti-Campath 1H response was detected. This preliminary study suggests humanized monoclonal antibody therapy may be of value in the treatment of rheumatoid arthritis.