Hydralazine autoimmunity

CYP450 antibodies leading to autoimmune hepatitis [68,69], Metabolic activation can also occur within the monocyte/macrophage and has been reported for many of the same xenobiotics (e.g., hydralazine) suggesting multiple mechanisms for xenobiotic autoimmune potential [68],... 

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. 

Nassberger, L. et al., Antibodies to neutrophil granulocyte myeloperoxidase and elastase Autoimmune responses in glomerulonephritis due to hydralazine treatment, J. Intern. Med., 229, 261, 1991. 

Deng, C. et al., Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling, Arthritis Rheum., 48, 746, 2003. 

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],... 

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... 

The drug hydralazine is a vasodilator used for the treatment of hypertension. In a significant proportion of individuals, it causes a serious adverse effect, drug-induced systemic lupus erythematosus (SLE). This is a systemic kind of toxic effect, as there is no particular target organ or tissue. It is an example of immune-media ted toxicity that involves autoimmunity and shows a number of interesting features. 

Pericarditis has been attributed to hydralazine in a 75-year-old man who developed a full-blown hydralazine-induced autoimmune syndrome (1). 

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 ... 

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... 

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. 

Other adverse effects are caused by immunological reactions, of which the drug-induced lupus syndrome is the most common. Hydralazine also can result in an illness that resembles serum sickness, hemolytic anemia, vasculitis, and rapidly progressive glomerulonephritis the mechanism of these autoimmune reactions is unknown. The drug-induced lupus syndrome usually occurs after at least 6 months of continuous treatment with hydralazine, and its incidence is related to dose, sex,... 

Methyldopa is the only antihypertensive drug associated with hemolytic anemia (usually preceded by a positive Coombs test). Hydralazine is also associated with autoimmune toxicity, but this takes the form of a lupus-like syndrome with butterfly facial rash, fever, joint and muscle pains, and antinuclear antibodies. The answer is (D). 

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). 

Yokogawa N, Vivino FB. Hydralazine-induced autoimmune disease comparison to idiopathic lupus and ANCA-positive vasculitis. Mod Rheumatol 2009 19(3) 338-47. 

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