Procainamide autoimmunity

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Drugs can cause a wide variety of other autoimmune reactions. One example is myasthenia gravis, which is characterized by muscle weakness and is mediated by antibodies against the acetylcholine receptor at the neuromuscular junction. It has been reported in association with penicillamine [66], gold salts [67], and procainamide [68]. Another form of drug-induced autoimmunity is polymyositis, which is an autoimmune disease... 

Only a few drugs have been identified as being capable of inducing autoimmune phenomena in mice. Among these are D-penicillamine, quinidine, streptozotocin (an anti-neoplastic drug that is also used as a model compound to induce diabetes) and procainamide. 

The dog is a species that is frequently used in toxicity studies. However, there are few reports in the open literature on dog studies with respect to chemical- or drug-induced hypersensitivity reactions or autoimmune effects, and those that are available lack consistency. For instance, procainamide has been shown to induce lupus-like symptoms (mainly an increase of ANA) in one study [63], but not in another study with younger dogs [64], Similar discrepancies have been observed for hydralazine-induced effects in dogs [5],... 

Propranolol Procainamide Pyrithioxine Autoimmunity Autoimmunity, drug-induced SLE, rash, vasculitis, myalgias Pemphigus... 

Autoantibodies to red blood cells and autoimmune hemolytic anemia have been observed in patients treated with numerous drugs, including procainamide, chlor-propaminde, captopril, cefalexin, penicillin, and methyldopa (Logue et al., 1970 Kleinman et al., 1984). Hydralazine- and procainamide-induced autoantibodies may also result in SLE. Approximately 20% of patients administered methyldopa for several weeks for the treatment of essential hypertension developed a dose-related titer and incidence of autoantibodies to erythrocytes, 1% of which presented with hemolytic anemia. Methlydopa does not appear to act as a hapten but appears to act by modifying erythrocyte surface antigens. IgG autoantibodies then develop against the modified erythrocytes. 

Certain autoimmune syndromes can be induced by drugs. Examples include systemic lupus erythematosus following hydralazine or procainamide therapy, "lupoid hepatitis" due to cathartic sensitivity, autoimmune hemolytic anemia resulting from methyldopa administration, thrombocytopenic purpura due to quinidine, and agranulocytosis due to a variety of drugs. As indicated in other... 

Studies of xenobiotic-induced immune dysregulation in animal models. Hydralazine and procainamide-induced autoimmunity HgClj and gold salt-induced autoimmunity The impact of genetic studies in our understanding of immunological-mediated toxic-induced renal disease ... 

Overall, however, the reason that only some patients develop autoantibodies, and that only some of those have hemolytic disease, is not known. In an effort to explain why patients may have a positive result from a Coombs test and no hemolysis, Kelton demonstrated that methyldopa impairs the abihty of these patients to remove antibody-sensitized cells. In Coombs-positive patients receiving methyldopa, patients with impairment of the reticuloendothelial system could not clear the RBCs coated with autoantibodies from their bloodstream, and therefore hemolysis did not occur. Patients with hemolysis had no impairment of the reticuloendothelial system. Procainamide has also been reported to cause a positive result on the direct anti-human globulin test and hemolytic anemia. Other drugs that have been reported to cause autoimmune hemolytic anemia include levodopa, mefenamic acid, and diclofenac. ... 

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. 

Acebutolol Alpha-methyl-dopa Captopril Carbimazole Chlorpromazine Dihydralazine Fludarabine Hydralazine Infliximab Interferons-alpha Iproniazid Isoniazid Nomifensine Penicillamine D-Penicillamine Practolol Procainamide Propylthiouracil rlL-2 Simvastatin Tienilic acid Tryptophan contaminants Zimeldine Lupus syndrome Autoimmune haemolytic anaemia Pemphigus ANCA-associated vasculitis Lupus syndrome Autoimmune hepatitis Autoimmune haemolytic anaemia Lupus syndrome, ANCA-associated vasculitis Lupus syndrome Wide range of autoimmune diseases Autoimmune hepatitis Lupus syndrome Autoimmune haemolytic anaemia Myasthenia, dermatomyositis Anti-GBM (Goodpasture) disease Oculocutaneomucous syndrome Lupus syndrome ANCA-associated vasculitis Autoimmune thyroiditis Lupus syndrome Autoimmune hepatitis Eosinophilia myalgia syndrome (see section 9.3.5) Guillain-Barre syndrome... 

Procainamide, widely used in the treatment of ventricular and supraventricular arrhythmias in the past, recently had its use restricted to short-term treatments due to the induction of autoimmunity and the development of drug-induced lupus (Ayer et al., 1993 Kretz-Rommel Rubin, 1999). It has been suggested that procainamide-induced autoimmunity is characterized predominantly by an antihistone and anti-denatured DNA immune response (Rubin et al., 1986 Rubin, 1992 Mongey Hess, 2001). Mechanistic studies have revealed that procainamide is a competitive DNMT inhibitor of some, but not all, nuclear methyltransferase activity (Scheinbart et al., 1991 Richardson, 2003). 

In general, autoimmune diseases persist for the life of the patient. They are often marked, however, by remission and exacerbation. Exceptions are seen in autoimmune conditions caused by drugs. For example, most cases of a lupus-like illness caused by procainamide or hydralazine usually resolve when the drug is discontinued. Some autoimmune diseases precipitated by an... 

Hydralazine and procainamide-induced autoimmunity HgCI2 and gold salt induced autoimmunity... 

We shall discuss hydralazine or procainamide-induced autoimmunity and heavy metal-induced immunopathological disorders because these compounds have been extensively studied using multiple experimental approaches and in several experimental systems, and because it was shown that several mechanisms may contribute to the development of autoimmunity. 

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). 

Disruption of Central Tolerance by a Reactive Metabolite of Procainamide Induces Autoimmunity in Mice... 

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