SYSTEMIC LUPUS ERYTHEMATOSUS-LIKE SYNDROME WITH FOCAL PROLIFERATIVE GLOMERULONEPHRITIS DURING D-PENICILLAMINE THERAPY

We report a patient with RA who developed serological evidencefor lupus disease in the presence of a crescentic immune complexglomerulonephritis (GN). This occurred after 4 years therapywith penicillamine and resolved on withdrawal of this drug andfollowing treatment with cyclophosphamide. KEY WORDS: Rheumatoid arthritis, Immune complex nephritis, Cyclophosphamide     

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.     

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.     

Discriminatory indices of response of patients with rheumatoid arthritis treated with D-penicillamine.

A long-term study is being undertaken to classify drugs used as specific agents in the treatment of rheumatoid arthritis in terms of their effects on biochemical and clinical characteristics of the disease. In particular is hoped to establish those indices which are most relevant to the response of RA to treatment. Fifteen patients were treated with D-penicillamine after an initial period of 2 weeks on aspirin alone, when the baseline investigations were made. The dose of penicillamine was increased gradually to a maximum of 500 mg a day over the period of 6 months, and changes in 8 clinical and 25 laboratory indices were measured on 8 separate occasions in the 6-month period. Marked clinical improvement took place, and this was mirrored by changes in a wide range of biochemical parametaers. ESR and C-reactive protein were shown to be the most suitable indices of disease improvement with penicillamine treatment.     

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.     

CRH test prior to discontinuation of long-term low-dose glucocorticoid therapy.

Often long-term low-dosage glucocorticoid therapy cannot be terminated. This is due to the fact that even low doses which are within the physiological replacement range can cause a detectable, though clinically insignificant suppression of the adrenal gland function, resulting in "corticosteroid withdrawal syndrome". Another reason is the fact that it is necessary to be able to suppress undesirable inflammatory reactions caused by the underlying disease. ACTH testing of the adrenal capacity is widespread, but repeated testing may lead to undesirable side effects, such as allergic reactions. This study investigates the usefulness of testing the function of the pituitary-adrenal axis in predicting withdrawal problems. In 21 patients with chronic inflammatory disease who were treated with glucocorticoid doses of 5 to 10 mg prednisolone equivalent daily for a period of 2 to 131 months, stimulation with 100 microg hCRH (human corticotrophin-releasing hormone) was performed prior to the gradual withdrawal of medication. Blood samples were taken at baseline and after 45 minutes to measure ACTH and cortisol levels. Four weeks after steroid withdrawal the patients were reevaluated for signs of a relapse of the underlying disease in order to establish the necessity of reintroducing steroid therapy. This reevalution comprised clinical criteria, laboratory tests and the patients' own assessment of his/her well-being. In sixteen patients who later successfully withdrew from glucocorticoid therapy, a significant increase in cortisal levels was noticed after stimulation with CRH (p < 0.05). In five patients, with whom steroid withdrawal was not successful, baseline levels of cortisol were significantly lower than in the others (p < 0.05) and no sufficient increase was achieved after stimulation with CRH. These results show that successful withdrawal of a long-term low-dosage glucocorticoid therapy depends on the integrity of the pituitary-adrenal axis. Therefore CRH testing for evaluation of the pituitary-adrenal axis can be helpful in identifying patients in whom glucocorticoid withdrawal would be troublesome.     

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.     

HLA system and penicillamine induced pemphigus in nine cases of rheumatoid arthritis.

Nine cases of penicillamine induced pemphigus (PIP) in rheumatoid arthritis patients are reported. Clinical, histological and serological data were compared with previously published cases. No correlation between the occurrence of HLA A, B, DR antigens and PIP was found, even when the data was combined with that from 13 cases described in the literature. The clinical and histological polymorphism of PIP and its unpredictable outcome are emphasized.     

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.     

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.     

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。     

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.     

Evolution of blood coagulation and fibrinolysis parameters after abrupt versus gradual withdrawal of acenocoumarol in patients with venous thromboembolism: a double-blind randomized study

A double-blind randomized trial was conducted to research a hypercoagulable state rebound after abrupt versus gradual withdrawal of acenocoumarol. 20 patients were included: 10 in the abrupt withdrawal group (AW) and 10 in the gradual withdrawal group (GW). Between days 1 and 15, F1+2 was higher in group AW ( P <0.002). A sig-nificant increase of D-dimer with time was found ( P <0.001) without difference between the two groups. tPA and PAI-1 levels remained stable throughout without difference between the two groups. No rebound phenomenon was observed. Four thrombotic recurrences were observed: group AW: 1, group GW: 3 ( P =0.29). There is neither clinical nor biological support for a gradual anticoagulation withdrawal.     

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.     

Comparison of penicillamine and gold treatment in early rheumatoid arthritis.

In a series of 100 adult patients with definite rheumatoid arthritis of at most 3 years' duration and with no previous penicillamine, gold or systemic corticosteroid treatment, 50 patients were treated with D-penicillamine and 50 with gold for one yar. The dose of penicillamine was 600 mg daily. Sodium aurothiomalate was given 50 mg weekly up to a total of 13 mg/kg and thereafter 50 mg once a month. In both treatment groups a statistically significant decrease in the number of painful and/or swollen joints, an increase in haemoglobin and a decrease in ESR, serum ceruloplasmin-, alpha1-acid glycoprotein-, IgG-, IgM- and IgA levels was observed. All the changes in these clinical and laboratory tests were of the same degree in both treatment groups. In the penicillamine group 12 out of 20 seropositive patients became seronegative and in another 5 the Waaler-Rose titre dropped clearly. In the gold group, 7 out of 16 seropositive patients became seronegative, and the Waaler-Rose titre dropped in another 5. An equal increase in the number of eroded joints in hands and toes was seen in the penicillamine and the gold group. Penicillamine was discontinued because of side effects in 13 patients (26%), and gold treatment in 15 (30%). Proteinuria and/or haematuria were the most common causes of discontinuation in the penicillamine group.     

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.     

A longitudinal study of pulmonary function in Danish patients with systemic sclerosis

Summary Objective: To determine the types, prevalence and development of respiratory abnormalities in patients with systemic sclerosis (SSc), and to correlate the results with clinical and serological findings. Methods: 176 patients with SSc observed longitudinally were retrospectively included in the study. The change per year of vital capacity (VC), forced expiratory volume in one second/vital capacity (FEV₁/VC), diffusing capacity (DLco) and diffusing constant (Kco) of carbon monoxide from the first till the latest pulmonary function test were correlated to clinical and serological findings, including anti-centromere, anti-Scl-70, and antinucleolar antibodies. Results: An isolated reduction of DLco was seen in 47% and a restrictive ventilatory pattern in 25% of the patients. Restrictive ventilatory pattern correlated to pulmonary fibrosis, dyspnoea, a low prevalence (13%) of anti-centromere antibodies and a high prevalence of anti-Scl-70 antibodies (36%). Progression of DLco reduction was related to long disease duration, presence of anti-centromere antibodies and absence of treatment with penicillamine. Conclusion: Pulmonary involvement is common in patients with SSc. The occurrence of different serological abnormalities in patients with restrictive disease and in patients with progressive isolated reduction of DLco, suggests that the two types of pulmonary damage may have different pathogeneses rather than being different stages in the progression of pulmonary damage.     

Diagnosis and management of Wilson's disease: results of a single center experience

AIMS: To report on the diagnostic features, management, and clinical outcome after different treatments of Wilson's disease patients followed over a mean period of 15 years. PATIENTS: Thirty-five patients with Wilson's disease referred to the University of Padova's Department of Gastroenterology for diagnosis or treatment were observed for a mean 15 years. The diagnosis was based on clinical symptoms, laboratory tests (ceruloplasmin, urinary, and hepatic copper concentrations), and uptake of the radiostable isotope Cu into the plasma protein pool. Hepatic Cu content was measured by regular follow-up biopsies. Neurologic outcome after therapy was assessed using a newly developed scoring system. RESULTS: Twenty-three (65.7%) patients presented with liver disease; 12 (34.3%) had mixed neurologic and hepatic involvement. All patients had been initially treated with either penicillamine (23) or zinc sulfate (12). The neurologic symptoms became worse or remained stationary in 75% of those treated with penicillamine, whereas zinc treatment improved these symptoms in 90% of treated cases. Both treatments were effective in improving the hepatic symptoms. No differences in hepatic Cu content emerged between follow-up biopsies in either treatment group. Six patients (26%) had to abandon the penicillamine treatment due to side effects. In all, 4 patients underwent liver transplantation, which was successful in 3, with a mean survival after transplantation of 4.6 years; the fourth, who had a severe neurologic impairment, died of central pontine myelinolysis. CONCLUSIONS: Penicillamine and zinc can effectively treat Wilson's disease, though the side effects of penicillamine may be severe enough to prompt its suspension. Liver transplantation remains the treatment of choice for end-stage liver disease.     

The biological meaning of anti-HBC positive result in blood donors: relation to HBV-DNA and to other serological markers

In order to assess the potential risk of anti-HBc-positive blood donors for post-transfusional hepatitis and to investigate whether other HBV serological markers are capable of identifying the presence of the virus, 1000 first-time blood donors were enrolled between June and July 1997. These donors were screened using routine Brazilian blood center tests (HIV 1 and 2, HTLV 1 and 2, Chagas disease, Syphilis, HCV, HBsAg, anti-HBc and ALT ). The 120 (12%) found to be anti-HBc-positive underwent further tests: HBe, anti-HBe, anti-HBs and HBV-DNA by PCR. Ten cases were HBsAg positive and all were HBV-DNA positive by PCR. Three HBsAg-negative donors were HBV-DNA-positive. Two HBV-DNA-positive donors were also anti-HBs-positive. All the HBV-positive donors had at least one HBV marker other than anti-HBc. Anti-HBc is an important cause of blood rejection. Testing for HBsAg alone is not fully protective and anti-HBc remains necessary as a screening test. The presence of anti-HBs is not always indicative of absence of the virus. The addition of other HBV serological markers could represent an alternative in predicting the presence of the virus when compared with PCR. It is recommended that other studies should be carried out to confirm this finding.     

Factors affecting the development of penicillamine side-effects.

Characteristics of patients on penicillamine therapy for rheumatoid arthritis were correlated with the occurrence of different side-effects. Patients developing proteinuria tended to have lower sheep-cell agglutination test titres prior to therapy, but no other correlations were found. It is postulated that rheumatoid factor reacts with immune complexes, causing their precipitation and reducing renal glomerular deposition and therefore the incidence of proteinuria. Penicillamine would surely be the first choice of anti-rheumatic therapy if it were not for its side-effects. It is capable of controlling the disease, but in many cases treatment must be interrupted because of some potentially serious side-effects, such as thrombocytopenia, rash or nephropathy. Understanding the mode of action of a drug may lead to the development of new and better compounds. Similarly, understanding the mechanism of the side-effects may lead to their elimination. This survey was designed to identify factors which influenced the development of particular side-effects in patients receiving penicillamine for rheumatoid arthritis.