Drug-Induced Immune-Complex Disease

Abstract

A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of Cl, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune- complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.

The use of a three compartment in vitro model to investigate the role of hepatic drug metabolism in drug‐induced blood dyscrasias.

“…Despite this bioactivation, we did not detect methaemoglobin formation in our test systems, in keeping with the in vivo observation that this drug does not cause red cell damage. The observation that the incidence of toxicity of both procainamide and hydralazine in vivo [29] is greater than that noted for dapsone may result from a lack of detoxication of the hydroxylamine metabolites by red cells.…”

Vasculitis in Cystic Fibrosis

“…In this, ANCA antibodies, that can be found in CF patients and that will be discussed in detail below, may be of special interest, as they contribute to increased bacterial colonization and their presence can contribute to IC formation (19). Furthermore, medications may stimulate ICs production or interfere with ICs clearance, thus leading to ICs accumulation and deposition (20). In particular, antibiotics such as penicillins and cephalosporins, can cause ICs deposition in blood vessel walls leading to the development of leukocytoclastic vasculitis.…”

Cornerstones of Toxicology

“…Patients with the highest plasma isoniazid levels were generally slow acetylators and they suffered from peripheral nerve damage, while fast acetylators were not affected (Goel et al , 1992). Slow acetylators are also at risk for sulfonamide-induced toxicity and can suffer from idiopathic lupus erythematosus while taking procainamide (Sim, 1989). The slow acetylator phenotype is an autosomal recessive trait.…”