Treatment of rheumatoid arthritis with penicillamine

Abstract

ENICILLAMINE is an active drug useful in the treatment of RA, but in some patients its use is associated with potentially hazardous adverse effects, in particular thrombocytopenia, some rashes, and proteinuria. It is a drug with much to offer, but our understanding of its place in the long-term treatment of RA is still in its infancy. Clinical problems are discussed in the light of personal experience with 109 patients observed for up to 3 yr-this group includes a yearlong two-dose comparative study. Indications for treatment, dosage, and management (including monthly mandatory urinanalysis and hematologic checks) are discussed. PHARMACOLOGY Penicillamine is &@dimethylcysteine-a sulphur-containing amino acid. It exists in the D or L form, the latter being considerably more toxic. It is invariably prescribed as D-penicillamine (DPA). Studies with3” S-labeled DL-penicillamine of synthetic manufacture in patients with Wilson’s diseaseI showed that absorption was rapid, with a peak blood level 1 hr after ingestion, followed by a rapid fall, although there were detectable amounts in the plasma at 48 hr. D-penicillamine is oxidized by the cytochrome system of the body and is then excreted as the disulphide. Pharmacologically, DPA is a very versatile drug (Table 1). In Wilson’s disease it forms stable chelates with copper and is the drug of choice in this otherwise invariably fatal condition. DPA forms similar chelates with other heavy metals and is successfully established as treatment for heavy metal poisoning. This led to its use in patients with RA who developed a toxic reaction to chrysotherapy, but in 1975 Jessop”’ found no evidence of increased urinary gold excretion and concluded that DPA is unlikely to be useful in the management of patients with gold toxicity. In cystinuria DPA forms mixed disulphides with cystine and cysteine, the solubility of the former being greatly increased, hence decreasing the risk of stone formation.4” The rationale for the use of DPA in active scleroderma is based on experimental and in vivo evidence which shows that DPA interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed.20’36 We are uncertain how DPA affects the course of RA, but its potential use stems from Jaffe’s observation 28 that DPA dissociated macroglobulins (rheumatoid factor) in the synovial fluid after intra-articular injection. From here pharmacology progressed to clinical use. The story is worth reporting in detail. HISTORICAL