Procainamide-induced Pleural and Pericardial Effusions

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More about the authors: From the 1) department of clinical pharmacy, University of Tennessee College of Pharmacy, Memphis, TN; 2) department of pharmacy, Veterans Affairs Medical Center, Memphis, TN; 3) department of medicine, University of Tennessee, Memphis, TN; 4) department of medicine, division of cardiovascular diseases, University of Tennessee, Memphis, TN; 5) division of cardiovascular diseases, University of Tennessee, Memphis, TN; 6) division of cardiovascular diseases, Veterans Affairs Medical Center, Memphis, TN.

INTRODUCTION

Drug-induced diseases and serious adverse drug effects can alter therapeutic plans and greatly affect patient outcomes. Many medications are known to have a narrow therapeutic index and to require close patient monitoring. These include several antiepileptic, anticoagulant, antimicrobial, and antiarrhythmic medications. Some medications can cause rare and potentially life-threatening adverse effects, such as agranulocytosis, thrombocytopenia, and hypersensitivity reactions. The likelihood of adverse effects, as well as precipitating risk factors, must be weighed as part of the risk-benefit equation at the time of therapy initiation. Difficulty arises, however, when a new disease or condition develops, and medication-induced changes must be considered.

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One adverse event that can be particularly problematic is drug-induced lupus erythematosus (DILE). Since 1945, when the first case of DILE was published in the medical literature, over 40 medications have been implicated to result in this complication. The most frequent offending agents include the antihypertensive medication hydralazine (brand name was Apresoline, which is no longer available in the United States) and the antiarrhythmic medication procainamide (Pronestyl). Patients with DILE often present with fever, arthralgias, and serositis. Sometimes patients have more unique presentations, such as asymptomatic pleural effusions, which can complicate a quick diagnosis. For example, in 1977, Curel and colleagues reported the case of a 63-year-old man who developed an asymptomatic pleural effusion following 6 months of procainamide therapy. Lupus erythematosus was initially suggested by the finding of lupus cells in the pleural fluid. The diagnosis of procainamide-induced lupus was confirmed when symptoms subsided and subsequent lupus cell testing was negative after drug withdrawal.

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Many adverse drug effects and drug-induced diseases are improved with medication withdrawal, while others may at least be halted. As for DILE, symptoms generally resolve within weeks of medication withdrawal; therefore, rapid identification of DILE is vital. Upon initiation of therapies or identification of a new disease, health care providers need to be aware of potential toxicities of medications and know how to limit the patient’s risk of adverse effects.

— Tracy E. Macaulay, PharmD, BCPS

Univ. of Kentucky Health Care,

Lexington, KY

References:

1. Vasoo S. Drug-induced lupus: an update. Lupus. 2006;15(11): 757-761.

2. Carel RS, Shapiro MS, Shoham D, Gutman A. Lupus erythematosus cells in pleural effusion: the initial manifestation of procainamideinduced lupus erythematosus. Chest. 1977;72(5):670-672.

3. Raebel MA, Carroll NM, Andrade SE, et al. Monitoring of drugs with a narrow therapeutic range in ambulatory care. Am J Manag Care. 2006;12(5):268-274.

Imaging in Cardiology

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Procainamide (Pronestyl) is a Vaughan-Williams Class IA antiarrhythmic agent useful in the treatment of supraventricular tachycardias, especially those associated with Wolff-Parkinson-White syndrome. Although not the most widely used antiarrhythmic agent, its adverse effect profile has been well documented. In 1962, Ladd reported the first case of drug-induced lupus erythematosus (DILE) resulting from procainamide, and this drug is now a well-known cause of DILE. There are currently 40 drugs in use that have been implicated in inducing a lupuslike syndrome. Procainamide has the greatest risk, and a lupus-like syndrome is estimated to occur in 29% to 35% of all patients receiving this agent. Symptoms of DILE include myalgias, arthralgias, fever, malaise, hepatosplenomegaly, common skin manifestations associated with systemic lupus erythematosus (SLE), and occasional cardiopulmonary findings, such as pericarditis or pleuritis. Compared with other agents that can cause DILE, pleural involvement is more commonly observed with procainamide-induced lupus, occurring in approximately 50% of patients. We report a case of DILE manifesting with pericardial and pleural effusions in a 62-year-old black man treated with procainamide for Wolff-Parkinson-White syndrome.

Case report

A 62-year-old black man presented to the emergency department with a 4-day history of worsening dyspnea. His medical history included Wolff- Parkinson-White syndrome with atrial fibrillation (AF), peripheral vascular disease, hyperlipidemia, arterial occlusive disease, peptic ulcer disease, arthritis, and depression. His surgical history included stent placement in the left superficial femoral artery 3 weeks earlier. On physical examination, the patient was found to have AF with a rapid ventricular response of approximately 140 beats per minute and a systolic blood pressure of 80 mm Hg.

The patient was alert, oriented, and afebrile, but mildly tachypenic with a respiratory rate of 25 breaths per minute. Chest auscultation revealed reduced breath sound intensity at both lung bases. Cardiac auscultation revealed normal S1 and S2 without any rubs or murmurs. The abdominal examination was unremarkable with no hepatosplenomegaly. Musculoskeletal examination showed mild swelling and tenderness of the elbow, wrist, and ankle joints bilaterally, which he started noticing several months before this admission. No skin rash was observed. He was electrically cardioverted to normal sinus rhythm, after which his blood pressure normalized and his breathing improved.

The patient’s chest radiograph showed an enlarged cardiac silhouette and bilateral pleural effusions (Figure 1), which had not appeared on his radiograph 1 month earlier. A computed tomography (CT) scan, performed to rule out the possibility of pulmonary embolus, showed a pulmonary embolus in the left upper lobe, moderate to large pericardial effusions, and bilateral pleural effusions. Extensive left lower extremity deep venous thrombosis was also noted (Figure 2). An echocardiogram was performed, which confirmed the presence of moderate to large pleural effusions (Figure 3). No signs of hemodynamic compromise were present, and his left ventricular systolic function was normal.

The patient reported complying with his medication regimen, which included procainamide ER (extended release) 1000 mg 3 times daily, and had been initiated 15 months earlier for intermittent AF in the presence of Wolff- Parkinson-White syndrome. He had refused ablation of his accessory pathway at that time. His other medications included the following: acetaminophen (Tylenol), 500 mg as needed for pain; acetylsalicylic acid (aspirin), 81 mg EC (delayed release) daily; citalopram (Celexa), 10 mg daily; clopidogrel (Plavix), 75 mg daily; divalproex sodium (Depakote, Epival), 500 mg ER every evening; pentoxifylline (Trental), 400 mg 3 times daily; and simvastatin (Zocor), 10 mg at bedtime.

Rheumatologic studies were positive for erythrocyte sedimentation rate, anti—single-stranded DNA (anti-ssDNA), antinuclear antibodies, histone, antihistone antibodies, and anti-Smith antibodies (Table 1). Lupus anticoagulant, anticardiolipin antibodies, and complement component 3 and 4 (C3 and C4) levels were negative, but the anti–double-stranded DNA (anti-dsDNA) was mildly positive. Additional laboratory values, including a complete blood count and serum creatinine, serum procainamide, and N-acetyl procainamide levels, were within normal limits.

Based on the clinical presentation and serologic studies, a diagnosis of DILE was made and procainamide was discontinued. Amiodarone (Cordarone) was started for maintenance of sinus rhythm. The patient was started on anticoagulation for his pulmonary embolus and deep venous thrombosis. No treatments for the pleural or pericardial effusions or the arthralgias were administered other than discontinuing procainamide.

The patient’s arthralgias resolved within 1 week of hospitalization, and pulmonary effects were markedly improved by 1 month without the use of anti-inflammatory medication. He remained clinically and hemodynamically stable and was discharged on amiodarone and warfarin after 4 days. A repeat CT scan with contrast 1 month later showed almost complete resolution of the pericardial effusion and significant improvement of the pleural effusion (Figure 4). Additionally, a repeat chest radiograph 2 months after discharge showed resolution of the pericardial and pleural effusions (Figure 5).

Discussion

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DILE aff licts approximately 15,000 to 20,000 people in the United States annually. Approximately 5% to 10% of systemic lupus cases result from drugs. Systemic lupus occurs predominantly in women, whereas DILE affects both sexes more equally. Whites develop both systemic lupus and DILE up to 6 times more frequently than blacks. Our patient’s case was a bit more uncommon because he is black. Other factors that increase the risk for developing DILE include the dose of the offending agent, duration of therapy, and the presence of slow acetylators phenotype.

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The exact mechanism of DILE is not completely understood and several hypotheses exist, including alterations in drug metabolism or immunologic pathways. Genetic predispositions may play a role in cases of drugs that are metabolized by acetylation. Patients with slow acetylators may be more likely to develop DILE than those with fast acetylators. Cases often occur after prolonged administration of the offending agent, and the onset may be acute or latent. True DILE usually occurs in patients who have a normal immune system and resolves after removal of the drug responsible.

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Clinical and laboratory differences between systemic lupus and procainamide- induced lupus are shown in Table 2. Most patients who develop DILE present with symptoms typical of systemic lupus, such as fever, weight loss, fatigue, and arthralgias. Kidney and central nervous system involvement are not as common with DILE as with idiopathic systemic lupus. Patients may infrequently present with blood dyscrasias, such as anemia, leukopenia, thrombocytopenia, or hypergammaglobulinemia, but these are usually mild in nature. In contrast to hydralazine-induced DILE cases, procainamide-induced lupus does not often manifest symptoms of arthritis or the malar skin rashes typical of systemic lupus. Pleural or pericardial effusions and myalgias, however, are more distinguishing findings associated specifically with procainamideinduced lupus. Symptoms may present acutely or in a more latent fashion and usually resolve a few days after stopping the offending agent.

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No absolute diagnostic criteria are available for confirmation of DILE, but laboratory evidence to support a diagnosis includes numerous tests. A positive antinuclear antibody test is present in virtually all patients with symptomatic DILE; however, its presence is not diagnostic without other clinical signs and laboratory abnormalities. Lupus erythematosus cells, antihistone antibodies, and the lack of antibodies to native, dsDNA help distinguish DILE from idiopathic systemic lupus. Antihistone antibodies are present in more than 95% of patients with procainamide- induced lupus. DILE cases generally have a higher frequency of anti—ssDNA antibodies, with rare presence of anti-dsDNA. Serum complement concentrations may be transiently low, but are usually normal in DILE. Elevated erythrocyte sedimentation rate is present in both idiopathic and drug-induced disease. Because there are no specific tests or criteria for making the diagnosis, some clinicians have suggested using the following 4 patient criteria to aid in diagnosis: (1) history of adequate exposure of a suspected drug; (2) temporal association with the administration of the agent and onset of lupus-like symptoms in a patient with no history of systemic lupus; (3) positive antinuclear antibody test and at least 1 clinical symptom of systemic lupus; and (4) improvement and remission of symptoms with a gradual decrease in antinuclear antibody concentrations once the offending agent has been discontinued.

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Drug-induced pleural effusions are most often caused by a drug-induced lupus-like syndrome. The most common agents implicated are procainamide, hydralazine, isoniazid (Nydrazid), quinidine (Quinaglute, Quinidex, Quinora), phenytoin (Dilantin), and chlorpromazine (Thorazine). Pleuritis caused by procainamide may be presumed by the presence of lupus erythematosus cells in the pleural fluid. Although we did not drain our patient’s effusions, druginduced disease was considered likely based on the serological results, clinical presentation, and improvement of the pleural and pericardial effusion after discontinuation of procainamide. It is important to note that drug-induced lupus pleuritis may persist for months or even years after discontinuation of the offending agent.

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Procainamide is often implicated in drug-induced pleural disease with effusion and should be considered as potentially causative in patients presenting with pleurisy. Although DILE symptoms usually resolve without treatment within days to weeks after discontinuation of the offending agent, antinuclear antibody tests may remain positive for months or years. If necessary, aspirin, nonsteroidal anti-inflammatory drugs, and antimalarial agents can be considered for short periods to relieve symptoms of arthralgias, myalgias, serositis, or skin manifestations. For more severe symptoms, such as pleuritis or pericarditis, short-term administration of low-dose steroids may be necessary.

Conclusions

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Procainamide-induced DILE is common, occurring in up to 35% of patients receiving this therapy. Although similar in presentation to systemic lupus, DILE has several key differences when it comes to risk factors, laboratory findings, and severity. In our patient’s case, procainamide was implicated as the cause of his pleural and pericardial effusions, and upon discontinuation of this therapy, his condition improved. The diagnosis of DILE should be suspected in any patients presenting with lupus-like symptoms and receiving a drug known to cause a lupus-like syndrome.

• Disclosure The authors claim no commercial or proprietary interest with the material presented.

References

1. Ladd AT. Procainamide-induced lupus erythematosus. N Engl J Med. 1962;267:1357-1358.

2. Lee KW, Normand MM. Syndrome resembling systemic lupus erythematosus. In: Tisdale JE, Miller DA, eds. Drug-Induced Diseases: Prevention, Detection, and Management. American Society of Health-System Pharmacists, Inc; 2005:57-68.

3. Rubin RL. Drug-induced lupus. Toxicology. 2005;209(2):135-147.

4. Vasoo S. Drug-induced lupus: an update. Lupus. 2006;15(11):757-761.

5. Grant DM, Mörike K, Eichelbaum M, Meyer UA. Acetylation pharmacogenetics. The slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver. J Clin Invest. 1990;85(3):968-972.

6. Byrd RP, Morris CJ, Roy TM. Druginduced pleural effusions. J Ky Med Assoc. 1991;89(2):71-73.

7. Harmon CE, Portanova JP. Druginduced lupus: clinical and serological studies. Clin Rheum Dis. 1982; 8(1):121-135.

8. Smith PR, Nacht RI. Drug-induced lupus pleuritis mimicking pleural space infection. Chest. 1992;101(1):268-269.induced systemic lupus, and procainamide DILE.