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.     

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.     

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.     

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.     

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.     

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.     

青霉胺和氨甲蝶呤联合治疗类风湿关节炎

用青霉胺和氨甲蝶呤联合治疗类风湿关节炎33例,并与单用青霉胺治疗的59例患者比较,结果显示临床缓解、显效、有效和无效的发生率在联合治疗组分别为24.2％,51.6％,24.2％和0;及在青霉胺组分别为18.6％,39.1％,25.4％和16.9％,经Ridir分析P<0.05。副作用发生率在两组分别为21.2％和16.9％(P>0.05)。结果提示,联合治疗的疗效优于单一青霉胺治疗的效果。     

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.     

The use of high-dose pulse methylprednisolone in rheumatoid arthritis. Unproved therapy

Pulse methylprednisolone therapy has been used for the treatment of rheumatoid arthritis. The recent literature describing pulse therapy for this disorder is reviewed. The effects of pulse steroids on the immune system, potential side effects of therapy, and recommendations for its use are presented. Because of the lack of substantial benefit and the possibility of adverse side effects, pulse methylprednisolone therapy should be considered investigational for short-term use in patients with aggressive rheumatoid arthritis undergoing induction therapy with long-term agents such as gold or penicillamine. More study is indicated before generalized use of this modality can be advocated.     

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.     

HLA antigens and toxicity to gold and penicillamine in rheumatoid arthritis

One hundred sixty-eight patients with rheumatoid arthritis treated with chloroquine (n = 87), gold salts (n = 133) and/or penicillamine (n = 77) were investigated for possible associations between HLA antigens and toxic reactions. Patients with 2 or more side effects to gold and/or penicillamine had a significantly increased frequency of antigens HLA-B8 and DR3 compared to patients with one or without adverse reactions. Proteinuria to gold or penicillamine was significantly associated with HLA-B8 (relative risk [RR] 4.2) and DR3 (RR 14.0) whereas nonnephrologic side effects to gold or penicillamine were associated with B7 and DR2 (RR 3.5 and 2.8). Patients with skin reactions to gold had a significantly greater frequency of HLA-B7. We found no correlation between chloroquine side effects and any HLA antigen. The results suggest a genetic predisposition to toxic reactions to gold or penicillamine based on an immunologic dysregulation.     

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.     

Reduced sulphoxidation capacity in D-Penicillamine induced myasthenia gravis

Summary Myasthenia gravis may be observed due to treatment with penicillamine (D-PA). The sulphoxidation capacity was measured in nine Swedish patients with rheumatoid arthritis (RA) who had developed myasthenia gravis toward D-PA. The results show that in eight of nine patients tested, this parameter was markedly reduced. A patient with poor sulphoxidation capacity has a twelve-fold greater risk of developing this rare side effect. The significance of this is discussed.     

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.     

DIFFUSE ALVEOLITIS ON A SMALL DOSE OF PENICILLAMINE

A 60-year-old man with seropositive rheumatoid arthritis developedrapidly progressive dyspnoea and bilateral pulmonary infiltrateson short exposure to 50 mg penicillamine daily. He made a satisfactoryrecovery following cessation of penicillamine therapy and theaddition of prednisolone. This case has been reported to the Committee on Safety of Medicinesand we would like to emphasize that the possibility of penicillamine-inducedlung disease should be recognized, even on a small dose of shortduration. KEY WORDS: Rheumatoid arthritis, Diffuse alveolitis, Penicillamine     

Respiratory failure due to a massive rheumatoid pleural effusion

A patient with rheumatoid arthritis (RA) and chronic obstructive lung disease was admitted with respiratory failure due to a massive pleural effusion. An extensive evaluation proved the effusion to be of rheumatoid origin. The effusion resolved with prednisone and penicillamine therapy. Although pleural effusions associated with RA are common, massive effusions are rare and respiratory failure from a rheumatoid pleural effusion has not been reported.     

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.     

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.     

Long-term treatment of rheumatoid arthritis with sulphasalazine, gold, or penicillamine: a comparison using life-table methods.

Life-table analysis was applied to the records of 317 patients with rheumatoid arthritis (RA) treated with sulphasalazine (SAS), 201 treated with sodium aurothiomalate (gold), and 163 with penicillamine. They comprised all those treated in our department with these drugs between January 1973 and July 1984. Risks of treatment termination for all reasons were similar for each drug at five years (gold 92%, penicillamine 83%, SAS 81%). The risk of treatment termination due to inefficacy was less for gold (29.5%) than for penicillamine (38.1%) or sulphasalazine (41.2%). Adverse effects, however, led to withdrawal of gold in 57%, penicillamine in 41.2%, and SAS in 37%; the most effective drugs appeared most toxic. Serious adverse effects were much more common in association with gold (17.4%) and penicillamine (12.3%) than with SAS (1.6%). Sulphasalazine appears as well tolerated over long periods in RA as gold or penicillamine and is associated with fewer serious adverse effects; of these drugs, it might therefore be considered the agent of first choice.     

Rheumatoid Vasculitis—Report of a Second Case Treated with Penicillamine

A 57-year-old man with rheumatoid arthritis and vasculitis is presented. His disease was characterized by neuropathy, episcleritis, gangrene, and a high serum titer of rheumatoid factor. His progressively deteriorating clinical course appeared to have been favorably influenced by penicillamine therapy, which also resulted in a marked fall in RF titer. He is now in his fourth year of remission, and is taking only this drug. He is the second patient with malignant rheumatoid disease to have shown a satisfactory response to penicillamine therapy.