Procainamide‐lymphocyte reactions. a possible explanation for drug‐induced autoimmunity

Abstract

Procainamide therapy has been associated with a lupus erythematosus (LE) like illness. At least 50% of patients who take the drug for a long time develop antinuclear antibodies and approximately 10% of these develop the complete clinical syndrome (1-3). There has been considerable speculation about the pathogenesis of the drug-induced disease. Most theories implicate drugnucleoprotein interactions, which result in the induction of antinuclear antibodies, but these explanations do not account for other autoantibodies often present in a patient with drug-induced lupus.The autoimmune phenomena of idiopathic lupus have been attributed to impaired immune regulation (4). To determine if similar mechanisms operate in the drug-induced syndrome, we looked for evidence of procainamide-induced lymphocyte abnormalities and found that many individuals taking the drug develop antibodies to cell surface antigens on normal lymphocytes. The frequency with which these antilymphocyte (ALA) antibodies develop and their concentration in the circulation are significantly increased in those patients with the procainamide-induced lupus syndrome. When the drug is discontinued, the antilymphocyte activity diminishes rapidly, in parallel with clinical improvement. We also found that procainamide alters the in vitro proliferative response of normal human lym- phocytes to mitogenic and antigenic stimulation. Taken together, these findings raise the possibility that procainamide induces the autoimmune lupus-like syndrome by its direct interaction with lymphocyte membranes. Clinical observationsSeventeen patients were identified as having procainamide-induced lupus as evidenced by a history of continued procainamide therapy, the development of new symptoms compatible with lupus, a serum antinuclear antibody titer of 1 : 10 or greater, and resolution of symptoms after discontinuation of the drug. The patients ranged in age from 49 to 83 years and 15 were male. The average total procainamide dose per patient in those with the drug-induced lupus syndrome was 695 gm, ranging from 60 to 1320.The clinical features of the procainamide-induced syndrome in our 17 patients included rheumatic complaints (arthralgia, diffuse myalgia, and arthritis) in 16; pleurisy or chest pain in 12; fever and weight loss in 7; and skin rash, mental confusion or headache, and Raynaud's phenomenon in 3 patients each. All subjects had a positive antinuclear antibody test, most with titers of 1 : 320 or greater. Serum antibodies to native doublestranded DNA (Farr technique) were not detected in any samples. Other immunologic abnormalities included positive direct and indirect Coombs tests, total leukocyte counts of less than 3000/mm3, and mild depressions in C3 or C4. A surprising finding was a circulating anticoagulant in 3 patients and an unexplained prolonged partial thromboplastin time (PTT) in another.

Antibodies to neutrophil granulocyte myeloperoxidase and elastase: autoimmune responses in glomerulonephritis due to hydralazine treatment

“…Similar findings have been reported with regard to discontinuation of procainamide treatment and the abrupt disappearance of lymphocytotoxic antibodies. The activity in all cases decreased after 3 to 1 6 weeks [15]. By contrast, IgG isotype anti-myeloperoxidase was found to persist at high concentrations, that were most pronounced after several years, despite clinical improvement.…”

Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro.

“…They proposed that antinucleic acid antibodies might appear in PA-treated patients as a consequence of a disorder of immune regulation resulting from a reaction between PA and lymphocyte membranes. In addition, this same group has reported that when PA was added to antigen-driven cultures of sheep erythrocyte-primed rabbit spleen cells, a prolonged antibody-forming cell response was observed (29). This experiment suggested that PA acted by altering suppressor T-cell circuits that may regulate this in vitro response.…”

Drug-Related Lupus

“…Lymphocytotoxic antibodies have been reported in DRL secondary to procainamide, hydralazine and certain anticonvulsants (Bluestein et al 1981;Hughes et al 1987).…”