Effect of D(-)penicillamine on chronic experimental arthritis in rabbits.

Preliminary observations on the effect of D(-)penicillamine on chronic antigen-induced experimental arthritis in rabbits are reported. Daily oral administration of penicillamine, at a dose equivalent to that usually administered to rheumatoid arthritis patients, diminished the arthritis in 2 out of 3 animals as assessed by both measurement of joint circumference and histological examination.     

Effect of penicillamine on complement in vitro and in vivo.

In most normal human sera the addition of penicillamine to a final concentration of 0-2 mmol/l and subsequent dialysis caused a slight reduction in serum haemolytic complement (CH50). At 200 mmol/l, CH50 activity was no longer demonstrable. Even high concentrations of penicillamine were needed to inhibit the ability of immunoglobulin to fix complement to preformed or forming immune complexes. This indicated that the reduction of CH50 observed in serum was due to an effect on the complement factors. In vivo, a dose of 240 mg penicillamine caused a slight transient reduction in CH50 in rabbit serum, while 1000 mg penicillamine had no effect on serum CH50 in patients with rheumatoid arthritis. In arthritis patients there was, however, some evidence for removal of complement deposits in synovial tissue during penicillamine treatment. Since it is theoretically possible that concentrations high enough to cause reduction of complement activity can be achieved locally in synovial tissue, the effect on complement may be one of the mechanisms by which penicillamine exerts its effect in rheumatoid arthritis.     

Insulin antibodies in patients receiving penicillamine

In a patient receiving penicillamine for treatment of rheumatoid arthritis, antibodies to insulin developed, which resulted in symptomatic hypoglycemia. When 30 additional patients receiving penicillamine were screened, another patient was discovered to have antibodies to insulin. The level of antibody fell sharply in both patients after penicillamine was discontinued. This particular immunologic reaction to penicillamine has not been reported previously.     

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.     

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.     

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.     

D-penicillamine withdrawal in rheumatoid arthritis.

Thirty-eight patients with rheumatoid arthritis in remission on penicillamine were entered into a prospective, randomised, placebo controlled study to determine the effects of gradual penicillamine withdrawal, to find a serological marker capable of predicting relapse, and to assess the effects of reintroduction of penicillamine. 80% of patients attempting gradual penicillamine withdrawal flared. There was no single serological marker capable of predicting outcome consistently. Decreasing SH levels were highly specific for recurrence of active synovitis but were insensitive. Reintroduction of penicillamine was successful. The implications of these findings, particularly concerning duration of therapy with disease modifying drugs, are discussed.     

Does second-line therapy affect the radiological progression of rheumatoid arthritis?

The effect of 'second-line' drugs on radiological progression in rheumatoid arthritis is not clear, and previous studies have yielded contradictory results. Sixty-seven patients with rheumatoid arthritis have been followed up clinically and radiologically for approximately 2 years (26 patients were receiving intramuscular gold, 21 penicillamine, 10 levamisole, and there were 10 controls who had consistently refused second-line therapy). Patients on gold and penicillamine showed improvement in erythrocyte sedimentation rate and haemoglobin over 2 years which was not seen in levamisole and control patients, but hand radiograph scores in all 4 groups showed statistically significant deterioration. There was a trend towards slowing of the rate of erosion in the gold and penicillamine groups in comparison with controls, but healing of erosions was extremely unusual.     

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.     

D-penicillamine and immune complex deposition.

Dense, granular immunoglobulin deposits have been identified at the epidermo-dermal junction in 4 out of 10 patients who developed toxic reactions to D-penicillamine therapy for rheumatoid arthritis. Three of 4 patients developing a lupus-like syndrome while on penicillamine had similar findings on skin biopsy. Serum immunoglobulin and complement levels decreased significantly in patients treated with penicillamine. It is suggested that, in addition to penicillamine nephropathy, other side effects of this drug may be related to widespread deposition of immune complexes.     

Gold vs D-penicillamine double blind study and followup

We undertook a controlled random double-blind comparing gold and penicillamine. Of the 50 patients with rheumatoid arthritis entered into the study, 34 completed the protocol. We found no significant differences in the clinical results, laboratory variables, or toxicity. Longterm followup of 55 months revealed that a significant number of patients were no longer on either drug. The notable exceptions were those who were felt to be in remission from either drug, and remained on gold, or penicillamine. No toxicity from penicillamine involving known immunological aberration has thus far been encountered.     

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.     

Eosinophilia in D-penicillamine therapy.

Cross-sectional and longitudinal studies have been carried out to determine the incidence and clinical significance of eosinophilia in patients taking penicillamine for rheumatoid arthritis. In a cross-sectional study of 204 patients eosinophilia was found with equal frequency during treatment with penicillamine, gold, and nonsteroidal anti-inflammatory drugs. A longitudinal study of 89 patients treated with penicillamine showed no consistent relationship between eosinophilia and adverse reactions to the drug. It is concluded that routine monitoring of eosinophil counts is unlikely to be of value in the management of patients taking penicillamine.     

Management of proteinuria secondary to penicillamine therapy in rheumatoid arthritis

Summary To determine if a policy of continuing penicillamine therapy in successfully treated patients with rheumatoid arthritis in the presence of persistent proteinuria, was associated or not with resolution of this adverse effect, a computer record of patients receiving penicillamine for rheumatoid arthritis was searched for patients with persistent proteinuria and the case notes of these patients reviewed. Eleven patients with persistent proteinuria were identified, eight of whom did not have nephrotic syndrome and were continued on penicillamine with close monitoring. In 5 patients proteinuria resolved after 16–21 months; 3 developed peripheral oedema (2) or worsening of pre-existing hypertension and proteinuria (1). In one of these the proteinuria subsequently resolved and one died of unknown cause. Of the 3 initially nephrotic patients, two had resolved at the time of the study. Persistent proteinuria in penicillamine-treated patients with rheumatoid arthritis resolves with continued therapy in the absence of nephrotic syndrome but vigilence is required for the development of any complications.     

Diffuse alveolitis on a small dose of penicillamine

A 60-year-old man with seropositive rheumatoid arthritis developed rapidly progressive dyspnoea and bilateral pulmonary infiltrates on short exposure to 50 mg penicillamine daily. He made a satisfactory recovery following cessation of penicillamine therapy and the addition of prednisolone. This case has been reported to the Committee on Safety of Medicines and we would like to emphasize that the possibility of penicillamine-induced lung disease should be recognized, even on a small dose of short duration.     

Cholestatic jaundice caused by D-penicillamine.

D-penicillamine is not generally considered to cause hepatic damage. Cholestatic jaundice developed in a patient with rheumatoid arthritis 4 weeks after penicillamine was added to his regimen, and he died in acute renal failure. The probability that penicillamine caused the cholestasis is discussed.     

Multiple side effects of penicillamine therapy in one patient with rheumatoid arthritis.

Skin rashes, proteinuria, systemic lupus erythematosus, polymyositis and myasthenia gravis have all been recorded as complications of penicillamine therapy in patients with rheumatoid arthritis. A patient who had developed all 5 is now described. The skin lesion resembled elastosis perforans serpiginosa, which has been reported as a rare side effect in patients with Wilson's disease but not in patients with rheumatoid arthritis treated with penicillamine.     

Effect of penicillamine treatment on immune complexes in two cases of seropositive juvenile rheumatoid arthritis

Bresnihan, F. P., and Ansell, B. M. (1976).Annals of the Rheumatic Diseases,35, 463-465. Effect of penicillamine treatment on immune complexes in two cases of seropositive juvenile rheumatoid arthritis. A correlation has previously been observed between the presence of enhancing complexes and cutaneous vasculitis in rheumatoid arthritis. Two patients with seropositive juvenile rheumatoid arthritis are described in whom enhancing complexes were detected before the appearance of cutaneous vasculitis. Their contrasting response to penicillamine is discussed in relation to the role of rheumatoid factor and antinuclear antibodies.     

Objective measurement of rheumatoid arthritis using technetium index.

The technetium index was measured in 22 patients with rheumatoid arthritis, before and after 6 months' treatment either with penicillamine or with anti-inflammatory drugs. The index was calculated by dividing the sum of the count rates over both knees and both wrists by the dose of technetium given. In the penicillamine group there was a significant reduction in the technetium index and the changes correlated well with some clinical measurements of improvement. It is suggested that the technetium index is a useful objective measure of the effects of drugs with a specific activity in rheumatoid arthritis.     

Sequential gold and penicillamine therapy in rheumatoid arthritis

Ninety patients with rheumatoid arthritis who had received courses of gold followed by penicillamine for their disease were evaluated to determine the predictiveness of a certain response or adverse reaction to gold for the same response or adverse reaction to penicillamine. Most patients who were considered gold-responders also responded to penicillamine, and most patients who did not respond to gold responded to penicillamine as well. Regarding toxicity, gold reactions did not predict reactions to penicillamine except that that patients with gold-induced proteinuria were at a higher risk for development of proteinuria during penicillamine therapy (p less than 0.001), and this usually occurred within the first six months of treatment. Patients with penicillamine-associated mucocutaneous reactions tended to have low gamma globulin levels (p less than 0.05) and were less likely to have subcutaneous nodules (p less than 0.05).