Purulent pericarditis in a patient with rheumatoid arthritis treated with etanercept and methotrexate

Case Reports

CJEM 2007;9(1):40-42

Abstract

Résumé

Introduction

Tumour necrosis factor-α (TNF-α) is a pivotal component of the inflammatory process.1 Agents that antagonize TNF-α activity are effective in the treatment of several inflammatory disorders, including rheumatoid arthritis (RA).2,3 Etanercept (Enbrel), a TNF-α antagonist, is a recombinant protein consisting of the extracellualar portion of the human TNF-α receptor fused to the Fc portion of human IgG1.4 Etanercept may result in immunosuppression, thereby increasing the risk of infection.5-7 We report a case of spontaneous purulent pericarditis in a patient with long standing RA treated with etanercept and methotrexate.

Case report

After a day of golf, a 71-year-old woman presented to a local resort clinic complaining of lower back pain with radiation to the right leg. While at the clinic she developed extreme abdominal pain and started vomiting. Her vital signs on presentation to the clinic were: heart rate, 92 beats/min; blood pressure 140/85 mm Hg; respiratory rate 18 breaths/min; and oxygen saturation, 99% on room air. She was afebrile, but pale and diaphoretic with cool extremities. Her chest, precordial and abdominal exams were all normal, and she had normal femoral pulses. The chest x-ray was normal. The ECG revealed Q-waves in the anterior leads. A presumptive diagnosis of ruptured abdominal aortic aneurysm or anterior myocardial infarction was made and she was flown by helicopter to our tertiary emergency department (ED).

On arrival at the ED, the patient was restless, distressed and complaining of extreme abdominal pain. Vital signs at this time revealed a blood pressure of 103/60 mm Hg, heart rate of 95 beats/min, respiratory rate of 30 breaths/min, pulse oximetry saturation of 93% on 12 L/min of oxygen, and a temperature of 37.5°C. She was pale and diaphoretic with cool extremities, but the remainder of her clinical examination was normal apart from a distended, diffusely tender abdomen with neither point tenderness nor peritoneal signs. Pulsus paradoxus was not assessed. She had no specific signs or symptoms that would identify a focus of infection or a bacterial portal of entry. A bedside portable ultrasound showed intraperitoneal free fluid, a thickened gallbladder wall, without evidence of stones or biliary dilation, and no aortic aneurysm. An incidental small pericardial effusion was noted.

Portable A-P chest x-ray was unremarkable, and the ECG showed generalized low amplitude and an anterior infarct of undetermined age. Arterial blood gases revealed a profound metabolic acidosis with inadequate respiratory compensation: pH 6.90; PaCO₂ 27 mm Hg; HCO₃ 5 mmol/L; base deficit 28 mmol/L; PaO₂ 83 mm Hg; and oxygen saturation 85% on 12L O₂ by mask. The initial hemoglobin, platelets, electrolytes, glucose, CK, troponin, INR and aPTT were all within normal limits. White blood cell count was 25.0 with 6.88 polymorphs and 9.61 bands. There was a severe anion gap acidosis with a lactate of 12.3 mmol/L. The creatinine was elevated at 178 mmol/L, but the urea was normal at 6.2 mmol/L.

Past medical history was remarkable for a 13-year history of RA that was well controlled by both methotrexate for 11 years and etanercept twice weekly for 2 years. The patient had a history of hypercholesterolemia, hypertension and a remote history of psoriasis. Her other medications included atenolol, clonidine, estradiol, rofecoxib (Vioxx) and ASA. Her only known allergy was to sulfa.

In the ED, she developed progressive respiratory failure and shock, requiring intubation and intensive care unit (ICU) consultation. Following intubation, she was fluid resuscitated and started on broad-spectrum antibiotics. Twenty minutes post-intubation, she suffered pulseless electrical activity cardiac arrest, received epinephrine and atropine. Spontaneous circulation returned after 2 minutes of cardiac compressions, and she was started on a dopamine infusion and sent for abdominal CT scan. This showed free fluid in the abdomen and pelvis with a thick-walled gallbladder, peripancreatic, pararenal and mesenteric fat stranding, bilateral pleural effusions, and a mild-to-moderate sized pericardial effusion.

Despite several liters of IV fluid, a dopamine infusion and repeated boluses of phenylephrine, the patient remained hemodynamically unstable requiring intermittent boluses of epinephrine to maintain blood pressure. At this time, the possibility of cardiac tamponade was considered and ED ultrasound-guided pericardiocentesis was performed. A total of 75 mL of cloudy, brown fluid was withdrawn and sent for gram stain and culture. The patient stabilized and was moved to the ICU. Gram's stain of the pericardial fluid showed 4+ polymorphs with gram-positive cocci, and cultures later identified methicillin sensitive Staphylococcus aureus (MSSA).

The patient's course in hospital included prolonged respiratory failure, septic shock and renal failure requiring dialysis. Following a 1-month stay in the ICU, she was transferred to the ward and discharged from hospital. The patient was advised to discontinue TNF-α antagonist agents and remain on the lowest possible dose of prednisone to control her RA.

Discussion

Purulent pericarditis is characterized by frank pus in the pericardial sac, usually as a result of direct surgical or traumatic inoculation with bacteria.8 It is rare in the post-antibiotic era; it is under-recognized; and it has a mortality rate approaching 100% if untreated.9,10 Most cases are associated with cardiothoracic surgery, cancer chemotherapy, uremia and, in rare instances, collagen vascular disease. The etiology may include hematogenous spread from a suppurative focus.11 A review of 425 cases of purulent pericarditis found that 40% were associated with pneumonia.12 The major infectious agents were Staphylococcus aureus and Streptococcus pneumoniae. The most common risk factor for Staphylococcus aureus was bacteremia.

New anticytokine therapy is effective in slowing the progression of RA and reducing medication doses.13 Clinical trials that lead to investigational new drug approval by the FDA (US Food and Drug Administration) and HPB (Health Protection Branch, Canada) may be too small to reveal rare but serious adverse effects associated with these new therapies; therefore, postmarketing surveillance is crucial. The FDA approved etanercept for the treatment of RA in November 1998. By August 2001, the FDA database showed that approximately 150 000 patients had been treated with this drug. Among these patients were 5143 reported cases (~3.4%) of new infections, including severe pneumonia, meningitis, sepsis, histoplasmosis and aspergillosis, resulting in 291 deaths. This rate is similar to published infection rates of 3%-9% per patient per year in RA sufferers; however, animals treated with etanercept have shown increased infection rates,14-16 and septic patients treated with etanercept for its anti-inflammatory properties have shown increased mortality.17

The occurrence of this highly unusual and severe infection in a patient receiving potent anti-inflammatory agents leads us to speculate that there may have been a causal link with the use of etanercept or methotrexate. The patient had no trauma or surgery, no injection drug use, no other apparent source of infection, no evidence of contiguous pneumonia, and no source of bacteremia to explain the purulent pericarditis.

Patients on anti-cytokine therapy must be monitored closely for signs and symptoms of infection, and advised to contact their physician immediately at the first sign of infection. The manufacturer recommends that etanercept be discontinued in patients with serious infections. Given that anti-cytokine therapy can mask symptoms of infection, thereby potentially delaying appropriate therapy,18 we also suggest aggressive investigation of even minor infectious symptoms, early antibiotic treatment, and discontinuation of anti-cytokine therapies, at least until an infectious etiology can be ruled out.

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