Low therapeutic value of D-penicillamine in a short-term prospective trial in primary biliary cirrhosis

A small double-blind controlled trial to evaluate the short-term effects of D-penicillamine therapy was carried out in 24 patients with primary biliary cirrhosis (PBC). The daily dose of D-penicillamine was increased monthly by 250 mg until a total of 1 g daily was reached. Two out of 11 patients (18%) were withdrawn because of side-effects, as also were 4 out of 13 (31%) patients receiving the placebo. Transient improvement in symptoms was observed in 4 of 11 patients on D-penicillamine, but also in 5 of 13 patients from the placebo group. The proportion of patients showing a fall in serum IgM, IgG and hepatic copper was significantly larger for the D-penicillamine group than for the placebo group. No improvement in liver tests was observed, but the progression of inflammatory periportal liver cell destruction (piecemeal necrosis) was retarded in patients on D-penicillamine (p = 0.02). Data analysis within the D-penicillamine group showed that lowering the dose of D-penicillamine to 500 mg daily abolished the effect on the serum immunoglobulins and hepatic copper. The beneficial effect of D-penicillamine therapy appears to be small and dose-related; side effects should not prevent its use, provided the drug is introduced slowly.     

Sulphasalazine in rheumatoid arthritis: Combination therapy with D-penicillamine or sodium aurothiomalate

Summary This open study examined the safety of adding a second slow-acting antirheumatic drug (SARD) — D-penicillamine or sodium aurothiomalate — to the therapy of 38 rheumatoid patients already established on sulphasalazine. Combined anti-rheumatic therapy given in this way was generally well-tolerated and the incidence of adverse reactions was not increased. During the first year none of the reactions were serious although 9 of the 29 patients (31%) given D-penicillamine and 3 of the 9 patients receiving aurothiomalate developed side-effects requiring withdrawal of the second SARD. Reactions attributed to D-penicillamine were: gastro-intestinal-6, rashes-2, and blurring of vision-1. All 3 reactions occurring with gold were rashes, 2 associated with proteinuria and one with increased liver enzymes. During the second year D-penicillamine was withdrawn in 4 patients due to thrombocytopenia-2, and rashes-2. In addition an overall favourable clinical response was achieved in 70% of patients. This approach for combination therapy whereby a second SARD is given to patients already established on a single SARD, appears to minimise the toxicity which is a problem when 2 SARDs are started simultaneously.     

Effect of D-penicillamine on the mechanical properties of aorta, muscle tendon and skin in rats

The biomechanical properties of rat aorta, muscle tendon and skin were studied after daily D-penicillamine treatment (500 mg/kg) for 5, 10 and 42 days. D-Penicillamine treatment for 5 days resulted in increased aortic extensibility. After long-term treatment the aorta exhibited a shift towards decreased extensibility and increased stiffness at small 'stress' values. Simultaneously the dry weight and diameter of the aortic samples were increased after D-penicillamine treatment for 42 days. After correction of the mechanical parameters for the increased amount of tissue of the samples, the stiffness at small 'stress' values was still increased and the mechanical stability at high 'stress' values retained. This is in contrast to the marked reduction in the strength of muscle tendon and skin of the same animals after D-penicillamine treatment for 42 days. This study demonstrates that a primary increase in the extensibility of aorta may elicit a reactive formation of vascular connective tissue. It is proposed that aortic smooth muscle cells are activated by an increased pulsatile distension of the vessel wall secondary to the early effect of D-penicillamine on collagen and elastin. The resulting excess deposition of collagen and elastin leads to increased stiffness, which may in turn increase the susceptibility of the aortic wall to hemodynamic injury. Consequently D-penicillamine may not as proposed counteract the development of atherosclerosis.     

Liver abnormalities in penicillamine treated rheumatoid arthritis.

Liver enzymes were followed in 99 patients treated with D-penicillamine for rheumatoid arthritis. In six abnormalities were found which consisted of elevated levels of lactic dehydrogenase. ALAT/ASAT, alkaline phosphatases or combinations of these. The changes were reversible on stopping the drug with one possible exception. No evidence of biliary cirrhosis, chronic active hepatitis or HBag-associated hepatitis was found. Liver biopsy was performed in 4 cases--one was taken 2 months after the treatment was discontinued, and was normal. One biopsy showed mild inflammatory changes, whereas in two histologic evidence of toxic liver necrosis was present. Liver damage should be included among possible complications of D-PA treatment.     

Effect of oral D-penicillamine treatment on experimental arthritis and associated immune responses in rabbits. III: Reduction of the monoarticular arthritis.

Treatment of rabbits with D-penicillamine at doses up to 30 mg/kg, beginning either before or after the onset of antigen-induced experimental arthritis, diminished the severity of the inflammatory synovitis in a considerable proportion of animals as judged by both external joint measurements and terminal histopathological assessment. D-penicillamine treatment had no effect on serum haptoglobin concentration, haemoglobin concentration, or platelet count. The venous blood white cell count was raised when D-penicillamine treatment was started before immunisation but not when treatment began after the onset of arthritis. A transient loss of appetite was observed in animals starting D-penicillamine treatment.     

Skeletal muscle pathology in 2 siblings infected with Toxoplasma gondii

Skeletal muscle can be the site of inflammatory diseases that lead to muscle weakness, pain, and increased myogenic serum enzymes. Most of these inflammatory myopathies are idiopathic. In some cases inflammatory myopathies are due to infectious agents. We describe the pathological aspects of muscle biopsies of 2 Brazilian siblings who acquired toxoplasmosis at the same time and in similar conditions. One developed a tetraplegia that was confirmed to be due to inflammatory myositis due to toxoplasma. The other developed myocarditis, with heart failure, without skeletal muscle weakness. In both cases many toxoplasma organisms were observed in the muscle biopsies, but in case 1 only was there an inflammatory myopathy with myofiber necrosis; the inflammatory cells were predominantly macrophages with some CD4+ cells and rare CD20+ cells. In case 1, expression of CD54 was observed in many inflammatory cells as well in endothelial cells, but only in endothelial cells in case 2. After treatment with clindamycin and corticosteroids both cases had only partial improvement, case 1 with a residual muscle weakness and case 2 with residual cardiac insufficiency (requiring digoxin). These cases show that the presence of the parasite in myofibers is not enough to induce an inflammatory myositis with muscle cell necrosis. This suggests that immunological disturbances may contribute to the development of inflammatory myositis due to toxoplasma.     

Effects of piroxicam and D-penicillamine on T lymphocyte subpopulations, natural killer cells and rheumatoid factor production in rheumatoid arthritis

The effects of piroxicam and D-penicillamine on T lymphocytes, NK cell activity and rheumatoid factor production as well as clinical parameters were studied in patients with rheumatoid arthritis. The level of total rheumatoid factor fell during treatment with D-penicillamine (p less than 0.02) and there was a positive correlation (K greater than 0.50, p less than 0.05) between this fall in rheumatoid factor and the improvement of several clinical activity parameters. No significant change was observed in the level of rheumatoid factor during treatment with piroxicam. Natural killer cell activity decreased from 21.1 +/- 2.5 to 15.8 +/- 1.9 after treatment with piroxicam for 3 weeks (p less than 0.05) as compared with changes in the controls. No change in natural killer cell activity was seen after treatment with D-penicillamine. Moreover, no significant changes in the numbers of T4+ and T8+ lymphocytes nor in the numbers of HLA-DR positive T cells were seen in the two treatment groups. Both laboratory and clinical activity parameters improved during the treatment with D-penicillamine, while only subjective parameters improved during treatment with piroxicam.     

Respiratory chain enzyme defects in patients with idiopathic inflammatory myopathy.

OBJECTIVE--To analyse muscle respiratory chain enzymes in idiopathic inflammatory myopathy. METHODS--Four consecutive female patients seen at our hospital with idiopathic inflammatory myopathy were studied. Muscle histochemical staining included NADH tetrazolium reductase and succinate dehydrogenase tests. Activity of rotenone sensitive NADH cytochrome c reductase (complex I and III) succinate dehydrogenase (complex II), succinate cytochrome c reductase (complex II and III), cytochrome c oxidase (complex IV), and citrate synthase (a mitochondrial matrix enzyme), was measured spectrophotometrically in muscle homogenates. Free carnitine, and short and long chain acylcarnitine esters were determined in muscle homogenates by a radiochemical procedure. RESULTS--Three patients had mitochondrial proliferation in nonregenerating muscle fibres; these patients had defects of respiratory chain enzyme complexes. Carnitine concentrations, measured in two of the four patients, revealed carnitine deficiency in one. CONCLUSION--Our results suggest that mitochondrial dysfunction may be present in patients with inflammatory myositis.     

Low-Dose D-Penicillamine Therapy in Rheumatoid Arthritis

Two hundred twenty-five patients with active severe rheumatoid arthritis were admitted to a multiclinic, controlled, double-blind trial comparing the use of 500 mg D-penicillamine per day, 125 mg D-penicillamine per day, and placebo. One hundred seventy-one patients completed at least 30 weeks of therapy. The 500 mg D-penicillamine group demonstrated statistically significant improvement over the placebo group in grip strength, average circumference of swollen proximal interphalangeal joints, and patient assessment. While the trend was for greater improvement with the larger dose of D-penicillamine, there was no statistically significant difference among the 3 groups in duration of morning stiffness, walking time, physician's assessment, number of swollen joints, or scores for tender and swollen joints. The slight increase in efficacy of higher dose D-penicillamine was associated with increased toxicity.     

Arthritis associated with a crystallizing cryoprecipitable IgG paraprotein

A crystallizing IgG-lambda cryoprotein was found in the synovial fluid of a patient with peripheral erosive arthritis and tenosynovitis. The same crystallizing paraprotein could be demonstrated in serum incubated at 4 °C, but its formation could be inhibited by the in vitro addition of D-penicillamine. Crystals were present in synovial tissue and appeared to be initiating an inflammatory reaction via complement activation. Slit lamp examination showed crystals in Bowman's membrane. Plasmapheresis led to temporary improvement in the synovitis and tenosynovitis.     

Auranofin or D-penicillamine in the treatment of rheumatoid arthritis

Ninety patients were entered into a randomized, controlled, double-blind trial lasting 12 months to compare auranofin (6 mg/d), and D-penicillamine (250 mg/d for 4 weeks, 500 mg/d for 4 weeks, then 750 mg/d thereafter) in the treatment of rheumatoid arthritis. Most patients in both groups completed the trial with significant improvement in all quantitative measures of efficacy. Patients treated with D-penicillamine were more likely to have "important improvement" in physician global assessment, swollen joint count, and score and grip strength. The overall frequency of side effects was similar between the two groups; however, more patients were withdrawn for adverse effects from the D-penicillamine group, and proteinuria (greater than or equal to 2+) and thrombocytopenia (less than 100 000 mm3) occurred significantly more frequently with D-penicillamine than auranofin (p = 0.028). These results suggest that in the dosage regimen used, auranofin is safer than D-penicillamine but that D-penicillamine tends to show greater clinical effectiveness in patients with rheumatoid arthritis.     

IMPAIRED SUPPRESSOR CELL ACTIVITY DUE TO SURFACE SULPHYDRYL OXIDATION IN RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a chronic inflammatory disorder withconsiderable evidence of impaired regulation of the immune response,including defective suppressor cell function, especially inthe synovial membrane. We have investigated whether oxidationof cell surface thiols might be responsible for these defectsand whether such cell function may be modulated towards normalby treatment with a sulphydryl-reactive drug, D-penicillamine. Using healthy mononuclear cells treated with an impermeant thiolblocker, induction of suppressor activity by incubation withthe lectin Con A was not dependent on surface sulphydryl groupsbut suppressor activity was abolished by thiol blockade afterCon A stimulation. Peripheral blood mononuclear cells from patientswith active rheumatoid disease showed impaired Con A-inducedsuppressor activity which was enhanced to near-normal levelsby incubating the rheumatoid cells with a sulphydryl reducingagent, 2-mercaptoethanol, or D-penicillamine. Con A-stimulationof cells from patients treated with intramuscular gold or D-penicillaminegenerated more active suppression than those from patients receivingnon-steroidal drugs only. Mononuclear cells from patients withother chronic inflammatory joint diseases showed normal ConA-induced suppressor activity. These data support the conclusion that surface thiols on mononuclearcells in rheumatoid arthritis are reversibly oxidized by thedisease process. This gives rise to aberrant cell function includingimpaired suppressor activity. Such a mechanism may be at leastpartly responsible for the defective immunoregulation seen inrheumatoid patients and thus be a relevant target for thiolcontaining antirheumatic drugs. KEY WORDS: Rheumatoid arthritis, Suppressor cell, Sulphydryl groups     

Muscle disease in progressive systemic sclerosis: diagnostic and therapeutic considerations

Upon careful examination, 23 of 24 patients with progressive systemic sclerosis (PSS) were found to have abnormalities of muscle. Nineteen patients presented a homogenous pattern of muscle abnormalities, which untreated was associated with a stable course ("simple myopathy"). Three patients demonstrated inflammatory muscle disease indistinguishable from polymyositis while a fourth patient developed marked weakness associated with a generalized neuropathic process. Muscle enzymes, electromyogram, and muscle biopsy permitted distinction among the different muscle disorders, a distinction that could have prognostic and therapeutic importance.     

Epidemiology, etiology and classification

Idiopathic inflammatory myopathies are a group of heterogeneous striated muscle acquired autoimmune diseases, characterized by progressive symmetrical muscle weakness, elevated serum levels of muscle enzymes, electromyographic abnormalities and inflammatory infiltrates on muscle biopsy. This group of diseases comprises polymyositis, dermatomyositis and inclusion-body myositis. They are considered rare autoimmune diseases, with an overall incidence range of 2 to 10 new cases per million persons at risk per year, with differences in distribution according to age, gender and race. Their etiology is largely unknown, but it likely involves both genetic and environmental factors that contribute to autoimmune disorders, with striated muscle as a common target.     

A deceptive case of amyloid myopathy: clinical and magnetic resonance imaging features

Amyloid myopathy is a well-described, increasingly recognized clinical entity. Similar to inflammatory myopathies, amyloid myopathy presents with proximal muscle weakness and can be associated with elevated levels of muscle enzymes. We report the case of a 58-year-old woman who, at presentation to her physician with proximal muscle weakness and congestive heart failure, was antinuclear antibody positive and had muscle biopsy findings "consistent with inflammatory myopathy." She was referred to Johns Hopkins University Medical Center with the diagnosis of polymyositis. Further investigation revealed a monoclonal gammopathy, a unique patterning of subcutaneous fat reticulation and hypodense bone marrow changes on magnetic resonance imaging (MRI), and an endocardial biopsy sample that was positive for light chain amyloid deposition. Paraffin sections of the muscle biopsy sample from the time of her original presentation were obtained, and Congo red staining showed diffuse amyloid deposition throughout the sample, but no inflammation. This case not only illustrates that proximal muscle weakness due to primary amyloid myopathy (as found in light chain amyloidosis and transthyretin amyloidosis) can mimic that of polymyositis, but also shows that unique findings on MRI can alert the clinician to the diagnosis of amyloidosis prior to muscle biopsy.     

Assessment of anti-inflammatory drugs in the rat using subcutaneous implants of polyurethane foam impregnated with dead tubercle bacilli.

The fluid and cellular phases of inflammatory resonse have been measured using a technique employing subcutaneous implantation of polyurethane foam cubes impregnated with heat-killed Mycobacterium tuberculosis. Phenylbutazone, azathioprine, aspirin, cyclophosphamide, and prednisolone suppressed fluid response, whereas sodium aurothiomalate, hydroxychloroquine, and D-penicillamine had no effect. All the drugs used suppressed the infiltration of inflammatory cells into the cubes.     

Muscle disease in progressive systemic sclerosis. diagnostic and therapeutic considerations

Upon careful examination, 23 of 24 patients with progressive systemic sclerosis (PSS) were found to have abnormalities of muscle. Nineteen patients presented a homogeneous pattern of muscle abnormalities, which untreated was associated with a stable course (“simple myopathy”). Three patients demonstrated inflammatory muscle disease indistinguishable from polymyositis while a fourth patient developed marked weakness associated with a generalized neuropathic process. Muscle enzymes, electromyogram, and muscle biopsy permitted distinction among the different muscle disorders, a distinction that could have prognostic and therapeutic importance.     

Morphea-like reaction to D-penicillamine therapy.

We report the case of a 48-year-old woman who developed morphea-like plaques after 1 year of treatment with D-penicillamine at 250 mg daily for a seronegative erosive arthritis of rheumatoid type. The rash began as several red itchy patches on the trunk; these became thickened and shiny over about 3 months. The histological appearance was of increased dermal fibrosis with an inflammatory infiltrate round dermal capillaries. However, epidermal changes were not typical of morphea. New lesions ceased to appear within a few months of stopping penicillamine, and by 1 year all the plaques were pale and symptomless.     

Is it really myositis? Mimics and pitfalls

Idiopathic inflammatory myopathies are a heterogeneous set of systemic inflammatory disorders primarily affecting muscle. Signs and symptoms vary greatly between and within subtypes, requiring supportive laboratory and pathologic evidence to confirm the diagnosis. Several studies are typical assessments for patients with suspected inflammatory myopathy, including muscle enzymes, autoimmune markers, imaging, and muscle biopsy. Misdiagnoses of myositis are not only related to the overlap of clinical phenotype with non-inflammatory myopathies, but also due to the limitations of diagnostic tests employed. Since many of the investigative tests are non-specific, they share features with other disorders, including muscular dystrophies, endocrine, toxic, and metabolic myopathies, and other neuromuscular or rheumatologic conditions. Recognizing the limitations of tests and understanding the shared features between inflammatory and non-inflammatory myopathies can help prevent misdiagnosing myositis with one of its several mimics.     

Inflammatory myopathies. Dermatomyositis, polymyositis, and inclusion body myositis

Idiopathic inflammatory myopathies are a group of heterogeneous, acquired systemic diseases characterized by progressive symmetrical muscle weakness, elevated serum levels of muscle enzymes, electromyographic abnormalities, and inflammatory infiltrates on muscle biopsy. Characteristic histopathologic features allow classification of idiopathic inflammatory myopathies into polymyositis, dermatomyositis, and sporadic inclusion-body myositis. These are commonly regarded as autoimmune disorders, and various autoantibodies directed to specific nuclear and cytoplasmic antigens are found. Other organs besides the muscle can be involved being the skin and lung the most frequent. Occasionally dermatomyositis and polymyositis can be associated with cancer in a paraneoplastic manner. Corticosteroids and immunosuppressive agents are the mainstay therapy, although in refractory cases biologic therapy can be used. Physical therapy can not be forgotten.