Antinuclear antibody procainamide

The answer is c. (Hardman, p 868. Katzung, pp 231—232) Procainamide blocks open Na+ channels. Long-term therapy can result in drug-induced lupus syndrome, identified by circulating antinuclear antibodies. Many patients may develop a facial rash and joint pains. Pericarditis can occur, but renal involvement is rare. 

Woosley, R.L. et al., Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome, New Engl. J. Med., 298, 1157, 1978. 

Balazs, T., and Robinson, C.J., Procainamide-induced antinuclear antibodies in beagle dogs. Toxicol. Appl. Pharmacol., 71, 299, 1983. 

The prolonged administration often leads to the development of a positive antinuclear antibody (ANA) test, with or without symptoms of a lupus erythematosus-like syndrome. If a positive ANA titer develops, assess the benefit/risk ratio related to continued procainamide therapy. 

Long-term drug use leads to increased antinuclear antibody titers in more than 80% of patients more than 30% of patients receiving long-term procainamide therapy develop a clinical lupus erythematosus-like syndrome. The symptoms may disappear within a few days of cessation of procainamide therapy, although the tests for antinuclear factor and lupus erythematosus cells may remain positive for several months. 

The main advantage of acecainide over procainamide is the lower incidence of the lupus-like syndrome. Many fewer patients develop antinuclear antibodies during long-term treatment with acecainide than during longterm treatment with procainamide (7). 

The antinuclear antibody is positive in virtually all cases and the ESR is often raised. Antihistone antibodies are also present in most cases. The prevalence of serum autoantibodies to high-mobility group (HMG) proteins in the serum of patients with drug-induced lupus-like syndrome varies from protein to protein 67% for HMG-14 and/or HMG-17 compared with 21% for HMG-1 and/or HMG-2. Procainamide-induced lupus is also associated with antibodies to the H2A-H2B dimer (55,56). 

Antinuclear antibody is usually present (in 83% of cases), but antibodies to native DNA are not found, although there may be antibodies to single-stranded DNA. Patients taking procainamide can have antinuclear antibodies without developing a lupus-like syndrome. 

A lupus-like syndrome has occasionally been reported in patients taking quinidine (60,61,64). It usually presents with polyarthralgia, a raised erythrocyte sedimentation rate, and a raised antinuclear antibody titer. It can occasionally be associated with antihistone antibodies and a circulating coagulant. In two cases (65) the syndrome was associated with quinidine and not with procainamide. Lupus anticoagulant has been reported with the use of quinine and quinidine, and an associated antiphospholipid syndrome has been described (66). 

Quinidine may be associated with a syndrome called cinchonism, which is characterized by headache, vertigo, and tinnitus. Procainamide may result in hypotension or a reversible syndrome similar to lupus erythematosus. Patients may develop positive antinuclear antibody (ANA) titers and complain of rash, arthralgia, and arthritis. Disopyramide is poorly tolerated due to its anticholinergic effects (urinary retention, dry mouth, blurred vision), and its use should be avoided in patients with congestive heart failure (CHF) due to negative inotropic effects. 

The exact phenotype of the regulatory T cells in the case of low-dose D-penicillamine tolerance is not known, and non-lymphoid cells probably play a role as well. In another example of drug-induced autoimmune responses, the phenotype of regulatory T cells was identified as CD4+CD25+ (Layland et ah, 2004). In this study, CD4+CD25+ cells isolated from mice (A/J strain) exposed to procainamide, mercuiy(II) chloride, or gold salts were capable of preventing antinuclear antibody formation in similarly treated recipient mice, but also in mice subsequently treated with one of the other two chemicals. 

Procainamide has been found to induce an increase in antinuclear antibodies in A/J mice after eight months of exposure via the drinking-water (Layland et al., 2004). This increase appeared mediated by CD4+CD25 T cells and regulated by CD4+CD25+ regulatory T cells. 

Dogs are a species frequently used in toxicity studies. However, there are only few reports in the open literature on dog studies with respect to chemical- or drug-induced hypersensitivity reactions or autoimmune effects, and studies are also often contradictory. For instance, procainamide has been shown to induce mainly an increase in antinuclear antibodies in one study (Balazs Robinson, 1983), but not in another study with younger dogs (Dubois Strain, 1972). Similar discrepancies were observed for hydralazine-induced effects in mice (Kammuller et al., 1989a). 

Some drugs such as hydralazine or procainamide may induce lupus like diseases with antinuclear antibodies and proteinuria. D-penicillamine not only causes glomerulopathies, but also myasthenia, polymyositis or lupus, suggesting that this compound provokes immune disregulation. Gold salts also are capable of inducing various immunopathological disorders such as pneumonitis, anemia, thrombocytopenia and hepatitis. 

Procainamide frequently results in a positive antinuclear antibody (ANA) test after prolonged... 

Due to their inhibitory effects on DNA methylation, procainamide and hydralazine can induce autoreactive T cells by upregulating the expression of lymphocyte function-associated antigen-1 (LFA-1), which causes the cells to proliferate in response to normally subthreshold stimuli, including self (Yung et al. 1995). As a result, the adoptive transfer of T cells modified by in vitro treatment with procainamide or hydralazine induces an autoimmune disorder characterized by antinuclear antibodies (ANAs) and immune complex glomerulonephritis in naive mice (Quddus et al. 1993). 

The mechanisms by which antinuclear antibodies are produced are not completely elucidated. It seems that the responsible drugs produce a lupus-like syndrome de novo rather than activating latent SLE. Hydralazine and procainamide... 

Davis DM, Beedle MA, Rawlins MD (1975) Antinuclear antibodies during procainamide treatment and drug acetylation. Br Med J 3 682 Delage C, Irey MS (1972) Anaphylactic deaths a clinicopathologic study of 43 cases. J Forensic Sci 17 525... 

Cubey RB, Taylor SH (1975) Ocular reaction to propranolol and resolution on continued treatment with a different beta-blocking drug. Br Med J 4 327-328 Dammin GJ, Nova JR, Rearden JB (1955) Hydralazine reaction case with L.E. cells ante mortem and post mortem and pulmonary renal splenic and muscular lesions of dissem-minated lupus erythematosus. J Lab Clin Med 46 806-809 Davies DM, Beedie MA, Rawlings MD (1975) Antinuclear antibodies during procainamide treatment. Br Med J 3 682-683... 

---