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.     

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.     

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.     

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.     

D-Penicillamine in rheumatoid arthritis

D-penicillamine was administered to 15 patients with rheumatoid arthritis. A fall in the titer of rheumatoid factor was demonstrated in all patients. The sedimentation rate decreased in most patients. There was no consistent alteration in immunoglobulins A, G or M or in lymphocyte transformation attributable to penicillamine. Ceruloplasmin serum levels were lowered significantly in 7 patients. Clinical improvement in the arthritis resulted in 10 patients.     

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.     

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.     

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.     

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.     

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.     

Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis.

Total plasma zinc levels in patients with rheumatoid arthritis on different therapeutic treatments were determined in conjunction with total serum proteins, serum albumin and globulin, and articular index of joint tenderness, erythrocyte sedimentation rate, rheumatoid factor, serum copper, and serum iron. There were significantly lower zinc levels in patients with rheumatoid arthritis on nonsteroidal anti-inflammatory drugs than in patients on levamisole and penicillamine. Zinc levels correlated positively with serum albumin, and there was an inverse correlation between zinc levels and both ESR and globulin concentration in all rheumatoid patients. However, the correlation coefficient varied in the different treatment groups. The results of this study support the hypothesis that low plasma zinc level in rheumatoid arthritis is one of the nonspecific features of inflammation.     

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.     

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.     

Rheumatoid arthritis: is serum vitamin B12 high in active disease?

Seven clinical and laboratory indices of disease activity were compared with serum vitamin B12 levels in 32 patients with rheumatoid arthritis treated with penicillamine (16 patients) or sulphasalazine (16 patients) for up to 24 weeks. Prior to treatment each patient had active disease but a normal or low serum vitamin B12 concentration. During treatment, significant improvements occurred in all clinical and laboratory measurements but vitamin B12 levels were unchanged. We have been unable to confirm a reported positive association between rheumatoid disease activity and serum B12 concentration.     

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.     

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.     

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.     

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.     

Microalbuminuria in patients with rheumatoid arthritis.

OBJECTIVES--To assess (a) the prevalence of microalbuminuria in patients with rheumatoid arthritis, (b) the association between urinary albumin excretion and disease activity as estimated by the erythrocyte sedimentation rate and C reactive protein (CRP), and (c) the association between urinary albumin excretion and treatment with antirheumatic drugs. METHODS--Sixty five patients with rheumatoid arthritis attending two rheumatology clinics were compared with 51 control subjects matched by age and sex. The controls consisted of 20 healthy subjects, 16 patients with osteoarthritis and 15 with non-articular rheumatism. Patients with hypertension, diabetes mellitus, or evidence of previous renal disease were not included. Urinary albumin was assayed by immunoturbidimetry in random urine samples on two occasions within seven months. The results were expressed as the ratio of urinary albumin to urinary creatinine ratio. Disease activity was assessed by the erythrocyte sedimentation rate and CRP. A drug history for the year before entry to the study was obtained for each patient. RESULTS--Urinary albumin to creatinine ratio in patients with rheumatoid arthritis was significantly greater than in controls (p < 0.01). Microalbuminuria (urinary albumin to creatinine ratio 3-30 mg/mmol in either or both urine samples) was present in 27.7% of patients with rheumatoid arthritis and 7.8% of the control subjects. A significant relation was noted between urinary albumin to creatinine ratio and CRP, and the duration of disease. The number of patients treated with either gold or penicillamine was significantly greater in patients with microalbuminuria than in patients with normoalbuminuria. CONCLUSIONS--Microalbuminuria is frequently present in patients with rheumatoid arthritis. Treatment with gold and penicillamine seems to increase the risk of developing microalbuminuria. Urinary albumin measured by immunochemical methods is a simple and sensitive test to detect early subclinical renal dysfunction and drug induced renal damage in rheumatoid arthritis. Urinary albumin excretion was found to be significantly correlated with CRP and may be a sensitive indicator of disease activity in patients with rheumatoid arthritis.     

Pharmacokinetic interactions of penicillamine in rheumatoid arthritis

The pharmacokinetic effect of the combined treatment of penicillamine with indomethacin and chloroquine was investigated in patients with rheumatoid arthritis. The mean plasma penicillamine concentration increased by 26% during indomethacin and 34% during chloroquine treatment. This new pharmacokinetic interaction may have important clinical implications.