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Penicillamine treatment of patients with rheumatoid arthritis (RA) leads to falling titers of agglutinating IgM rheumatoid factor (RF), but its effect on IgG RF has not been described. Using specific solid phase radioimmunoassays, we have determined serial levels of IgM RF and IgG RF in 18 patients receiving penicillamine for 1 year, and correlated the results with the change in RA activity. Mean IgM RF levels fell to 76 +/- 10% (mean +/- SEM) after 3 months, and 30 +/- 5% of the pretreatment value after 1 year of penicillamine treatment. This decline was greater than that for total IgM (P less than 0.0001), indicating a selective reduction of RF. Patients receiving maintenance doses of 750 mg/day manifested more rapid and greater decreases than did those given 250 mg/day. In contrast, serial mean IgG RF levels did not change significantly, and actually increased in 6 of 18 cases. At onset, there was a significant correlation with erythrocyte sedimentation rate for both IgM RF (r = 0.535, P = 0.05) and IgG RF levels (r = 0.570, P = 0.02). But changes in RF concentration demonstrated no correlation with changes in either erythrocyte sedimentation rate or joint score over the 1-year period, suggesting that circulating IgM RF or IgG RF levels may be unrelated to the degree of RA activity.

A series of mercaptan compounds were studied with respect to their ability to inhibit the growth of poliovirus in cultured cells. Of the compounds tested only d-penicillamine possessed antiviral activity. There was no direct effect on the virus itself, nor were the processes of adsorption, penetration and uncoating, or virus-induced "shut-off" of host cell protein synthesis inhibited. At concentrations where there was no effect on host cell RNA or protein synthesis, d-penicillamine caused a marked inhibition of virus-specific RNA and protein synthesis. Although much reduced, the relative concentrations of single-stranded and double-stranded viral RNA synthesized in the presence of d-penicillamine was unchanged. Similarly, all apparent precursor and cleavage product proteins could be synthesized in the presence of the drug. The inhibitory effect was reversible, after a lag of 1.5 to 2 h after removal of the drug, and normal yields of virus could be obtained. The structural and functional properties of d-penicillamine are discussed in relation to requirements for anti-polioviral activity.

The current status of the clinical pharmacology of penicillamine was reviewed. Its indications in the therapy of RA were defined, and current principles of dosage were presented. The autoimmune side effects were discussed in the light of their possible implication with regard to a locus of action of the drug on the immunological system. A comparison was presented of the biochemical properties of penicillamine and 5-thiopyridoxine, another mercaptan compound which appears to demonstrate a penicillamine-like action in patients with RA. It was found that 5-thiopyridoxine did not possess copper chelating properties, it failed to form a mixed disulfide with cystine, it did not induce dermolathyrism in the weanling rat, and it was not a vitamin B6 antagonist. If both of these compounds do work by a common mechanism in RA, then the aforementioned biochemical properties of penicillamine must be presumed to be not relevant to its fundamental action in this disease.

Penicillamine-associated bullous eruptions share with spontaneously occurring pemphigus intraepidermal acantholysis, epidermal intercellular deposition of immunoglobulin, and circulating serum antibody against the intercellular regions of the epidermis. We report the case of a penicillamine-associated bullous eruption in which there were some of the histologic features of pemphigus, but none of the immunofluorescent features. Instead, the immunofluorescent findings of bullous pemphigoid were demonstrated. Review of the literature reveals that clinical and histologic features of penicillamine-associated bullous eruptions differ in important respects from those of spontaneously occurring pemphigus. Our report adds immunologic data to evidence that the penicillamine-associated bullous eruptions may not be the same disease as spontaneously occurring pemphigus.

Autoimmune diseases, including myasthenia gravis, occur in patients treated with D-penicillamine. Because D-penicillamine might induce autoantibodies by the mechanism of antigenic alteration, we studied the reaction of D-penicillamine with purified acetylcholine receptor from Torpedo californica. We found that brief exposure to D-penicillamine resulted in its covalent attachment to two receptor subunits, alpha (40,000 daltons) and gamma (59,000 daltons), presumably by reduction and formation of mixed disulfides. Furthermore, D-penicillamine treatment resulted in a dramatic modification of the equilibrium acetylcholine binding properties of both purified receptor and receptor-rich membrane fragments.

Protein-bound homocyst(e)ine was measured in the plasma of 38 nonhomocystinuric patients with rheumatoid arthritis. Nineteen of them were treated orally with D-penicillamine 100-1,500 mg/d for a period of one month to 15 years. For these patients, the mean +/- standard deviation level of plasma protein-bound homocyst(e)ine was 1.95 +/- 1.07 nmol/mL. In contrast, the mean plasma level of protein-bound homocyst(e)ine was 4.72 +/- 1.11 nmol/mL in the 19 patients who had not been treated with oral D-penicillamine. There was a statistically significant difference (P less than .0001) in the plasma protein-bound homocyst(e)ine concentrations between patients with and without oral D-penicillamine therapy. Thus, it may be speculated that oral D-penicillamine may be beneficial in protecting patients from the development of thromboembolism and arteriosclerosis.

Penicillamine is now established as a useful disease remittive drug in the treatment of rheumatoid arthritis. Improvement during a successful course of treatment may be found in a decrease in the degree of synovitis, which is associated with a reduction in the level of rheumatoid factor and immune complexes in serum and synovial fluid. Vasculitic lesions also resolve. There is roentgenographic evidence of healing of the erosive lesions after two to three years of treatment. The multiplicity of adverse effects caused by the drug limits its usefulness, although with increasing experience more patients are being treated successfully. The induction of autoimmune side effects in a small number of patients treated with penicillamine has elicited particular interest since this may represent a clue to its mechanism of action on the immune system. The over-all approach to the use of the drug, including currently accepted methods of dosing and safety monitoring, is reviewed.