Pericardial tamponade: A presenting manifestation of procainamide-lnduced lupus erythematosus

Procainamide, a frequently used antiarrhythmic agent, may produce a syndrome clinically indistinguishable from idiopathic lupus erythematosus. Pericarditis with or without effusion is occasionally a prominent manifestation of the disease, but cardiac tamponade is exceptional.The patient described had a clinically evident and laboratory confirmed drug-induced syndrome complicated by an unusually severe pericarditis with effusion and tamponade necessitating pericardiocentesis. Treatment with prednisone produced impressive amelioration of the pericarditis with no recurrence of the lupus erythematosus syndrome during a prolonged period of observation following cessation of corticosteroid therapy. Prompt initiation of steroid treatment in drug-induced lupus erythematosus complicated by massive pericardial effusion is strongly suggested by this experience.     

Constrictive pericarditis in procainamide-induced lupus erythematosus syndrome

A rare case of constrictive pericarditis in procainamide-induced lupus erythematosus syndrome is reported. After 6 months of procainamide therapy fever, pleuritic chest pain, arthralgia and muscle soreness developed in a 47 year old man. These symptoms were soon followed by the onset of acute pericarditis and rapidly accumulating massive pericardial effusion. After withdrawal of procainamide therapy and administration of corticosteroids in large doses, there was marked subjective improvement and rapid reduction in pericardial effusion. However, constrictive pericarditis with massive leg edema and ascites developed 6 weeks after admission as corticosteroid therapy was gradually discontinued. These manifestations subsided after pericardiectomy was performed.     

Procainamide-induced lupus erythematosus pericarditis encountered during coronary bypass sugery

Procainamide is probably the most common offending drug responsible for the drug-induced lupus erythematosus syndrome today. Pericarditis has been reported to occur in from 14 to 18 per cent of the cases of procainamide-induced lupus erythematosus, and occasional reports of massive pericardial effusion, pericardial tamponade and constrictive pericarditis have appeared in the literature. We describe a patient who presented with features of procainamide-induced lupus erythematosus without any clinical evidence of pericarditis. He underwent coronary bypass surgery 12 days after administration of the drug was stopped and was found to have a significant pericardial effusion at the time of surgery; histologic examination of pericardial tissue and pericardial fluid confirmed that the pericardial effusion was related to the procainamide-induced lupus syndrome. The incidence of pericarditis in procainamide-induced lupus erythematosus may be higher than presently accepted figures would indicate. Symptoms and signs related to procainamide-induced lupus pericarditis may cause diagnostic confusion with common postoperative bypass complications; the full implications of this disease entity to the patient undergoing coronary bypass are unknown.     

Drug-Induced Lupus Erythematosus Presenting With Cardiac Tamponade: A Case Report and Literature Review

The presentation of drug-induced lupus erythematosus (DILE) is typically mild, with a significantly lower incidence of life-threatening end-organ dysfunction relative to idiopathic systemic lupus erythematosus. DILE is an uncommon cause of cardiac tamponade but has been reported in patients treated with procainamide, isoniazid, hydralazine, sulfasalazine, and carbamazepine. We present a case of DILE presenting with cardiac tamponade associated with infliximab use that resolved with discontinuation of the medication and administration of high-dose steroids. In conclusion, DILE should be considered in the differential diagnosis in cases of pericarditis with cardiac tamponade without a clear cause.     

Late toxicity to hydralazine resembling systemic lupus erythematosus or rheumatoid arthritis

Of 371 patients with hypertension who were observed for two months to 20 years and who were initially treated with from 100 to 1,600 mg of hydralazine daily, late toxic manifestations to the drug developed in 44. They were serious in 14. The course of such toxicity is presented, with emphasis on factors predisposing to the syndrome and on the long-term course of oncetoxic patients, including the results of readministering hydralazine to them. Among drug-induced diseases, late hydralazine toxicity is of peculiar interest because of its clinical similarity to idiopathic lupus erythematosus and rheumatoid arthritis. The syndrome, however, is a relatively benign one; the toxic manifestations are reversible when the drug is withdrawn, and the arthritis is not deforming. Several interesting observations concerning the toxicity have recently been made: first, only that half of the population with a low level of hepatic acetyl transferase activity is susceptible to clinical hydralazine toxicity; second, both antihydralazine antibodies, suggesting hypersensitivity, and antiDNA antibodies, suggesting lupus erythematosus, are demonstrable in toxic patients; third, significant remissions of serious hypertension, although rare, seem to occur more frequently in once-toxic patients; and fourth, survival time from the onset of therapy is suggestively better in toxic patients than in similarly treated, matched patients with no history of toxicity.     

Drug-induced lupus erythematosus

Drug-induced lupus is a syndrome which share symptoms and laboratory characteristics with the idiopathic systemic lupus erythematosus (SLE). The list of medications implicated as etiologic agents in drug-induced lupus continues to grow. The terms used for this condition are lupus-like syndrome, drug-induced lupus erythematosus (DILE) and drug related lupus. More than 80 drugs have been associated with DILE. The first case of DILE was reported in 1945 and associated with sulfadiazin. In 1953 it was reported that DILE was related to the use of hydralazine. Drugs responsible for the development of DILE can divided into three groups, but the list of these drugs is quite long because new drugs are included yearly in the list. The syndrome is characterised by arthralgia, myalgia, pleurisy, rash and fever in association with antinuclear antibodies in the serum. Recognition of DILE is important because it usually reverts within a few weeks after stopping the drug.     

Drug-Induced Glomerular Disease: Immune-Mediated Injury

Drug-induced autoimmune disease was initially described decades ago, with reports of vasculitis and a lupus-like syndrome in patients taking hydralazine, procainamide, and sulfadiazine. Over the years, multiple other agents have been linked to immune-mediated glomerular disease, often with associated autoantibody formation. Certain clinical and laboratory features may distinguish these entities from their idiopathic counterparts, and making this distinction is important in the diagnosis and management of these patients. Here, drug-induced, ANCA-associated vasculitis, drug-induced lupus, and drug-associated membranous nephropathy are reviewed.     

Prospective study of immune response to hydralazine and development of antideoxyribonucleoprotein in patients receiving hydralazine

To examine the relationship between the immune responses to hydralazine, a drug known to induce systemic lupus erythematosus, and to deoxyribonucleoprotein (DNP) we followed prospectively 21 hypertensive patients treated with hydralazine for the first time. Within one year, antibodies to hydralazine developed in 16 of these patients and anti-DNP in seven of these. In one patient whose serum had a positive antinuclear antibody test prior to treatment, a mild hydralazine systemic lupus erythematosus syndrome developed preceded by rises in the levels of both anti-hydralazine and anti-DNP. Studies by radioimmunoassay on serums of three additional patients, not followed in this study but known to have hydralazine-induced systemic lupus erythematosus, revealed no evidence for either (1) cross-reactivity between anti-DNP and anti-hydralazine or (2) antibodies specific for a hydralazine-DNP complex. In some way, perhaps related to the mechanism by which carrier molecules enhance the immunogenuity of haptens, hydralazine increases the antigenicity of DNP. This effect depends on the development of immunity to hydralazine as well.     

Acute hydralazine overdose: marked ECG abnormalities in a young adult.

Although hydralazine is a commonly prescribed antihypertensive agent, reports of acute human poisoning are uncommon. Most of the literature focuses on chronic toxicity, most notably, the drug-induced systemic lupus erythematosus syndrome. A case of acute hydralazine overdose associated with marked ECG ST segment depression in a young adult is presented. Although the patient also had mild hypotension, acidemia, and ethanol intoxication, the ECG abnormality was alarming and suggestive of myocardial ischemia. The patient was managed conservatively in an ICU setting, and the metabolic and ECG abnormalities resolved. No reports of such marked ECG changes associated with acute hydralazine poisoning in a young adult could be found. Clinical and experimental data on acute hydralazine exposure suggest that the possibility of direct drug effects, including positive inotropic and chronotropic effects and myocardial cell injury, should be considered.     

Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling

OBJECTIVE: To determine whether hydralazine might decrease DNA methyltransferase (DNMT) expression and induce autoimmunity by inhibiting extracellular signal-regulated kinase (ERK) pathway signaling. METHODS: The effect of hydralazine on DNMT was tested in vitro using enzyme inhibition studies, and in vivo by measuring messenger RNA (mRNA) levels and enzyme activity. Effects on ERK, c-Jun N-terminal kinase, and p38 pathway signaling were tested using immunoblotting. Murine T cells treated with hydralazine or an ERK pathway inhibitor were injected into mice and anti-DNA antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: In vitro, hydralazine did not inhibit DNMT activity. Instead, hydralazine inhibited ERK pathway signaling, thereby decreasing DNMT1 and DNMT3a mRNA expression and DNMT enzyme activity similar to mitogen-activated protein kinase kinase (MEK) inhibitors. Inhibiting T cell ERK pathway signaling with an MEK inhibitor was sufficient to induce anti-double-stranded DNA antibodies in a murine model of drug-induced lupus, similar to the effect of hydralazine. CONCLUSION: Hydralazine reproduces the lupus ERK pathway signaling abnormality and its effects on DNMT expression, and inhibiting this pathway induces autoimmunity. Hydralazine-induced lupus could be caused in part by inducing the same ERK pathway signaling defect that occurs in idiopathic lupus.     

Provocation of myocardial ischemic events during initiation of vasodilator therapy for severe chronic heart failure: Clinical and hemodynamic evaluation of 52 consecutive patients with ischemie cardiomyopathy

Although hydralazine provokes myocardial ischemie events in hypertensive patients not in heart failure by producing reflex tachycardia, the frequency of and mechanisms underlying ischemie events when this drug is administered as a vasodilator agent to patients with heart failure is unknown. The responses to hydralazine in 52 consecutive patients with severe chronic heart failure secondary to coronary artery disease were reviewed. Twelve patients (23 percent) had 16 ischemie events during the initial administration of hydralazine (angina at rest in 12 and myocardial infarction in 4); these generally occurred in the absence of significant tachycardia and hypotension. Thirty-five of the 52 patients received nitroprusside (8 of whom had ischemie events with hydralazine), but this drug provoked ischemia in only 1 of the 35 although it resulted in greater decreases in systemic arterial pressure than occurred with hydralazine. In patients with an ischemie event only with hydralazine, left ventricular filling pressure decreased 14.6 mm Hg with nitroprusside but only 3.9 mm Hg with hydralazine (probability [p] < 0.01). Provocation of ischemia with hydralazine may therefore be due to the relative preservation of elevated left ventricular preload with this drug, since ischemie events are not common with nitroprusside despite greater decreases in systemic pressures.     

Laryngeal manifestations of drug induced lupus

Respiratory stridor and hoarseness were the predominant presenting symptoms in a 63-year-old woman with an hydralazine induced lupus syndrome. Laryngeal tomograms and direct laryngoscopy were consistent with cricoarytenoid arthritis. Proteinuria, anemia, arthritis, and leukocytoclastic vasculitis, as well as the laryngeal findings, all resolved after withdrawal of hydralazine. Laryngeal manifestations of systemic lupus erythematosus are reviewed.     

Immunologic effects of hydralazine in hypertensive patients

Twenty-seven hypertensive patients (23 blacks, 4 whites) treated with hydralazine had frequent serologic evidence of autoimmunity. However, only 1 patient developed a lupus syndrome. Acetylator phenotype influenced the autoimmune response; slow acetylators had a higher incidence and titers of autoantibodies. The lupus patient not only had high titers of autoantibodies but they were predominantly IgG in contrast to the predominant IgM antibodies found in other slow acetylators. Hydralazine treatment did not alter cell-mediated immune responses and hydralazine antibodies were not detected. However, half the patients tested who received hydralazine had positive lymphoproliferative responses to the drug.     

Quinidine induced lupus syndrome

Five patients with a lupus-like syndrome secondary to quinidine are described. Eleven other cases have previously been reported. The quinidine induced lupus syndrome is similar to that seen with procainamide and hydralazine treatment but occurs less frequently. The lower incidence may reflect a difference in the metabolism of quinidine. Quinidine should be considered as potentially responsible when multisystem disease appears in patients receiving this drug.     

Aromatic amines and the pathogenesis of lupus erythematosus

The acetylation pathway of drug metabolism is the pathway by which aromatic amines and hydrazines are metabolized. Hydralazine and procainamide are aromatic amines or hydrazines that are metabolized by this pathway. Persons who are genetically slow acetylators are predisposed to development of lupus from these two drugs, suggesting that the free amine or hydrazine moiety is the inciting agent. When acetylprocainamide was given as an antiarrhythmic drug to patients with procainamide-induced lupus, the disease went into remission, indicating that the free amine group on procainamide had induced the disease. The genetic acetylator phenotypes of persons with idiopathic lupus were studied, and an excess of genetic slow acetylators was observed. This suggests amines or hydrazines induce some cases of this disease. One patient was identified with a lupus-like illness due to occupational exposure to hydrazine itself.     

Nephrotic syndrome and immune complex glomerulonephritis associated with chlorpropamide therapy

Therapeutic drugs are well-recognized as a cause of the nephrotic syndrome in humans. However, documentation of the renal histopathologic features is lacking or incomplete in many cases. Even when accurate histopathologic information is available, there is little evidence to support a specific pathogenetic mechanism of renal injury in the vast majority of cases. We describe a patient with diabetes who had hepatitis and dermatitis in association with the use of chlorpropamide. In addition to these well-described toxic reactions to this drug, the nephrotic syndrome developed. Renal biopsy revealed the presence of a proliferative glomerulonephritis that was shown to be of an immune complex nature on immunofluorescence and electronmicroscopic study. Serial serum complement levels and circulating immune complex levels were consistent with an immunologically mediated reaction. Repeated renal biopsy documented resolution of the renal changes. Thus, in this patient, a drug-induced nephrotic syndrome was associated with a proliferative glomerulonephritis, probably due to the formation of immune complexes.     

Current incidence of postmyocardial infarction (Dressler''s) syndrome

This study examines the current incidence of postmyocardial infarction (Dressler's) syndrome. During 1980, 282 patients with documented myocardial infarction were admitted to our coronary care unit. Early postmyocardial infarction pericarditis was present in 18 patients (6.4%). Six of these patients received steroids and the remainder were treated with salicylates or other anti-inflammatory drugs. Anticoagulation was used in 149 patients (53%) during hospitalization. One hundred forty-four (51%) were receiving heparin and 133 (47%) received no anticoagulation. Information on the patient's status at 6 months was available in 229 patients who were discharged alive. Sixteen patients had died within 6 months after discharge and 4 patients were lost to follow-up study. There were no documented cases of Dressler's syndrome.

It is concluded that Dressler's syndrome has decreased in incidence and perhaps disappeared. This decrease is most likely related to decreased use of oral anticoagulants and to more aggressive treatment of postmyocardial infarction pericarditis.     

The myocardiopathies of systemic lupus erythematosus]

Myocardial involvement in lupus erythematosis takes the form of an interstitial myocarditis with cellular infiltration and fibrinoid necrosis. The most lesions are perivascular, and involve the arterioles. The myocardial fibres are involved secondarily to the vascular lesions, or by grossly, damaging sclerosis. The clinical features are variable:--no clinical features, but haemodynamic evidence of abnormal ventricular function, and perhaps sudden death;--arrhythmias and disorders of atrio-ventricular conduction;--cardiac failure, which may be due to a genuine cardiomyopathy (a part may be played by hypertension, pulmonary hypertension, renal failure, constrictive pericarditis or haemodynamically major valve disorders);--abnormalities of the coronary trunk in a certain number of cases. If anti-nuclear antibodies are present in a cardiomyopathy, the presence of DLE or of a drug-induced lupus syndrome must be suspected. There remain some awkward cases which defy classification, and which systematic use of echocardiography and pericardial and myocardial biopsy may be able to define more accurately.     

Reactive hypoglycemia and insulin autoantibodies in drug-induced lupus erythematosus

An 82-year-old woman developed symptomatic reactive hypoglycemia in the same year she developed a lupus-like syndrome, probably secondary to the administration of procainamide or hydralazine. Reactive hypoglycemia was confirmed by an oral glucose tolerance test, in which plasma glucose decreased from a fasting level of 87 mg/dL to 32 mg/dL at 3 hours and 23 mg/dL at 4 hours, the last value being associated with loss of consciousness. The patient awoke after the intravenous administration of dextrose. Sensitivity to exogenous insulin was normal or increased. Attempts to measure plasma insulin levels led to the finding of anti-insulin antibodies in the patient's serum; these antibodies were of relatively low titer, were IgG, and not associated with antibodies to the insulin receptor. The patient had no history of exogenous insulin use. Her reactive hypoglycemia appeared due to the autoimmune insulin syndrome, which developed in association with drug-induced lupus erythematosus.     

Neutrophilic dermatosis (Sweet's syndrome). Association with a hydralazine-induced lupus syndrome

Neutrophilic dermatosis (Sweet's syndrome) is a condition that presents with arthritis and a skin rash. A case report is presented, and an association with hydralazine and lupus is described.