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     

THE EFFECT OF CONTINUING PENICILLAMINE AND GOLD TREATMENT ON THE COURSE OF PENICILLAMINE AND GOLD NEPHROPATHY

The effect of continuing penicillamine or gold treatment wasexamined in 53 patients with biopsy proven penicillamine (32)or gold (21) nephropathy. Thirty-two patients stopped penicillamineor gold treatment as soon as proteinuria was detected whilst21 patients continued treatment for periods of 2-11 months.The 24-hour creatinine clearance and urinary protein excretionwere measured serially for a median period of 6 years. No significantdifferences were observed in the initial or maximum proteinuria,the duration of the proteinuria or in the initial or latestcreatinine clearances between the groups of patients. Theseresults indicate that penicillamine or gold treatment may becontinued for short periods under close supervision despitemoderate proteinuria without causing permanent renal damage.As several alternative non nephrotoxic agents are availablefor the treatment of rheumatoid arthritis, continued treatmentwith penicillamine or gold despite proteinuria is seldom indicated. KEY WORDS: Rheumatoid arthntis, Penicillamine and gold nephropathy, Continued treatment, Renal function     

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.     

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.     

Prospective trial of penicillamine in primary sclerosing cholangitis

We evaluated the therapeutic efficacy of penicillamine in primary sclerosing cholangitis. In a randomized, prospective, double-blind trial, 39 patients received penicillamine (250 mg t.i.d.) and 31 received a placebo. The two groups were highly comparable at entry with regard to clinical, biochemical, radiologic, and hepatic histologic features. Although a predictable cupruresis and a decrease in levels of hepatic copper were achieved in patients taking penicillamine, there was no beneficial effect on disease progression within 36 mo or on overall survival. Progressive symptoms, deterioration in serial hepatic laboratory values, or histologic progression on sequential liver biopsy specimens were similar in both groups, occurring in greater than 80% of the entire study population. The development of major side effects led to the permanent discontinuation of penicillamine in 21% of the patients taking the drug. We conclude that the use of penicillamine in primary sclerosing cholangitis is not associated with a beneficial effect on disease progression or survival, and has considerable toxicity. The study also suggests that primary sclerosing cholangitis is a progressive disease in many patients.     

The effect of penicillamine on blood pressure and vascular disease in mice with infarct-kidney hypertension.

Treatment with penicillamine was capable of bringing down the elevated systemic arterial pressure in the thymus-dependent phase of infarct-kidney hypertension in mice; a marked improvement in the clinical condition of the treated animals was observed as compared with untreated hypertensive mice. No pathological changes in either kidney or heart could be attributed to toxic side effects of penicillamine either in normotensive or in hypertensive mice treated for several months with penicillamine. It is concluded that penicillamine may have an effect on thymus-dependent reactions, such as the increased blood pressure in the chronic phase of infarct-kidney hypertension in mice. In mice, the treatment can be extended over a considerable part of the animal's life span without apparently giving rise to toxic side effects on vital organs.     

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.     

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.     

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.     

Gold and penicillamine: a proposed mode of action in rheumatoid arthritis, based on synovial fluid analysis.

Although in common use, there is still controversy as to the way in which gold and penicillamine act in rheumatoid arthritis (RA). In this study, synovial fluids from 4 groups of patients have been compared: (1) RA patients on gold/penicillamine, (2) RA patients on non-steriodal anti-inflammatory drugs (NSAID) only, (3) osteoarthritis patients, and (4) patients with sero-negative arthropathies. The parameters measured were differential agglutination titre (DAT), total haemolytic complement (CH50), total protein, total white cell count, and immunoglobulins. RA patients on gold/penicillamine have lower synovial DAT levels and higher CH50 levels than RA patients on NSAID only, and total and cryoprecipitable IgM levels very close to those found in the sero-negative joint fluids. The non-specific inflammatory parameters, ie, white cell count and total protein are unchanged after good/penicillamine therapy. In a second study, the serum DATs of patients in total remission after gold/penicillamine were compared with similar patients on NSAID only. The DAT falls significantly in the former group (P less than 0.001), but not in the latter suggesting that fall in DAT is a consequence of therapy rather than remission. The parameters altered by gold/penicillamine in the synovial fluid are those that distinguish RA from non-rheumatoid arthropathies suggesting the drug's primary effect is to render the disease sero-negative. The results support the hypothesis that both drugs have a common mode of action based on their active thiol groups, and that the fall in DAT is due to the reduction of the antigenicity of the IgG complexes.     

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.     

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.     

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).     

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.     

In vitro penicillamine competition for protein-bound gold(i)

The reactions of penicillamine with gold sodium thiomalate (Myochrysine), gold-albumin complexes, and gold bound to urinary and kidney cytosolic proteins were examined. Large excesses of penicillamine (20 to 100: 1 penicillamine/gold ratios) are required to mobilize significant amounts of protein bound gold. Quantitative comparisons of cysteine and penicillamine displacements of serum albumin bound gold indicate that penicillamine is approximately 5–6 times more effective than cysteine. Uninary gold is observed to be present in low molecular weight and protein bound forms, which exist in a labile chemical equilibrium and can be shifted by addition of penicillamine. These results are discussed in terms of the structure of gold(I)-penicillamine complexes and the distribution of gold(I) among protein and nonprotein thiol groups. The inappropriateness of using AuCl₄⁻ in vitro to study the biochemistry of chrysotherapy agents is delineated.     

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.     

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.     

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。