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A 58-year-old woman presents to the hospital reporting fatigue, swelling of the legs and feet, and shortness of breath. She explains that her symptoms have been getting worse over the past 2 months.

Her medical history includes hypertension and rheumatoid arthritis (RA), which was diagnosed 5 years previously. Since her RA diagnosis, she has received several treatments, beginning with methotrexate. Records show that 2 years later (3 years before presenting at the hospital), she was converted to leflunomide (a cell cycle inhibitor). However, she explains that her arthritis symptoms had become bothersome again over the past year, resulting in the addition of tumor necrosis factor (TNF) inhibitor therapy with golimumab about 4 months prior to her presentation at the hospital.

At the time of her admission, she is receiving hydroxychloroquine, prednisone, leflunomide, and golimumab to manage her rheumatoid arthritis.

Physical examination identifies evidence of active arthritis; elevated jugular vein pressure; and significant pitting edema of her lower extremities. An erythrocyte sedimentation rate obtained prior to admission was 27 mm/h (normal: <30), and she is negative for citrullinated peptide antibody.

Post-admission work-up

• White blood cell count: 15 K/μL (normal range: 3.80-10.80)
• Creatinine: 1.7 mg/dL (normal: 0.6-1.4)
• Total bilirubin: 4.8 mg/dL (normal: 0-1.2)
• Troponin 0.11 ng/mL (normal: <0.05)
• N-terminal pro B-type natriuretic peptide: 5,070 pg/mL (normal: <125)

Results of a computerized tomography (CT) scan suggest that the patient has probable cirrhosis, based on evidence of a nodular liver.

An electrocardiogram reveals an ectopic atrial tachycardia. Finally, clinicians obtain a transthoracic echocardiogram that identifies a pericardial effusion 2.5-cm in circumference, with right ventricular diastolic collapse and a possible mass compressing the right ventricle.

Treatment and outcome

Pericardiocentesis is performed and 320 cc of hemorrhagic fluid is removed. Potential etiologies to explain the patient's pericardial effusion – including malignancy and mycobacterial and fungal infections – are not detected on analysis.

A follow-up transthoracic echocardiogram confirms successful resolution of the effusion. However, findings are suggestive of a constrictive process and thickened pericardium. Clinicians performed a cardiac magnetic resonance imaging (MRI) scan with gadolinium contrast. This identifies a 3.5-cm soft tissue mass within the pericardial sac that is compressing the right ventricle (Figure).

The patient undergoes median sternotomy for removal of pericardial mass and further investigation. The procedure reveals that both left and right cardiac chambers are encased by thick (6-8 mm), fibrotic, partially calcified pericardium.

The pericardium is resected laterally to within about 2 cm of the course of the phrenic nerve. Examination of the pericardial mass notes a friable organized collection of fibrous material with tanned cauliflower-like appearance over the anterior part of the heart near the atrioventricular groove.

Pathologic evaluation of the pericardial mass reveals a 7.2 × 6 × 1-cm mass with acellular fibrinous debris and cholesterol clefts; however, there is no evidence of inflammation, malignancy, infection, or granuloma nodules. The pericardium appears fibrotic with evidence of chronic inflammation.

Case follow-up

The patient is subsequently discharged, at which time golimumab is discontinued.

Serial follow-up echocardiograms are performed up to 26 months after surgery, and there is no evidence of re-accumulation of pericardial effusion or recurrence of a pericardial mass.

Discussion

Clinicians reporting this ¹ of a woman with stable rheumatoid arthritis (RA) who develops subacute right ventricular compression secondary to a pericardial effusion and a fibrotic mass note that pericardial involvement is uncommon in stable RA. Furthermore, they add, fibrotic pericardial masses in this setting are even more rarely described.

Rheumatoid arthritis is a chronic inflammatory disease that generally affects the synovial membrane, but may have extra-articular manifestations, including cardiac involvement. The most common cardiac manifestations of rheumatoid arthritis are pericarditis, pericardial effusions, myocarditis, coronary vasculitis, diastolic dysfunction, and valvular heart disease.²

Case authors note that the patient's joint disease and rheumatic markers were stable when she presented at the hospital. Given their clinical and diagnostic findings, they suggest that the pericardial mass and effusion were probably not caused by active rheumatoid arthritis, opportunistic infection, or malignancy. Thus, based on the evidence [or lack thereof], authors suggested a possible causative relationship between anti-TNF treatment and the patient's development of pericardial fluid and mass.

The group cites a 2013 review of reported cardiac abnormalities in patients with rheumatoid arthritis that did not identify any patients with fibrotic pericardial mass development.³

However, the authors' own review of the literature to address this possibility identified three patients with rheumatoid arthritis documented to have intrapericardial fibrous masses.^4-6

Typically, causation is suggested to be inflammation and extra-articular rheumatoid disease; one patient had active arthritis. Interestingly, they noted, one patient had been treated with leflunomide, and two other reports did not specify the treatment regimen.

Authors of this case refer to four other cases in which pericardial effusions have been reported as a possible adverse effect of TNF inhibitor use.^7-10 These included two cases of pericardial effusions in patients on anti-TNF therapy, both with surgical drainage. Another case report described pericardial effusion that improved dramatically following discontinuation of adalimumab therapy.

Finally, they reference a entitled "Pericardial effusions on anti-TNF therapy for rheumatoid arthritis – a drug side effect or uncontrolled systemic disease?" describing seven patients who developed pericardial effusion on anti-TNF therapy.

Proposed explanations for in RA patients¹¹ include autoimmune reaction to a TNF inhibitor; paradoxical flares of systemic rheumatoid arthritis secondary to anti-TNF therapy; drug-induced lupus; and cutaneous/systemic vasculitis, case authors write.

Pericardial effusion might be expected from TNF therapy with golimumab, case authors suggest, although they are not aware of any similar reports to date. Laboratory studies in mice have noted that TNF inhibitors can contribute to murine myofibroblast proliferation,¹² they add.

The exact cause of pericardial effusion and fibrotic lesions remains uncertain, case authors note. Leflunomide – which has been associated with interstitial lung disease and pulmonary nodule formation¹³ – cannot be excluded as a potential cause of intrapericardial mass.

However, pointing to their patient's long-term (and uneventful) exposure to leflunomide therapy, and comparatively brief 4 months of golimumab therapy prior to her presentation, these clinicians opine that there may be a causative association between the use of TNF inhibitors and the development of pericardial effusion and fibrotic pericardial masses.

References

1. Okajima K, et al: Rheumatoid arthritis and cardiac compression caused by a Large fibrotic intrapericardial mass and effusion: A case report. Am J Case Rep 2019; 20: 1120-1123

2. Voskuyl AE: The heart and cardiovascular manifestations in rheumatoid arthritis. Rheumatology (Oxford) 2006; 45(Suppl. 4): iv4–7

3. Corrao S, et al: Heart involvement in rheumatoid arthritis: Systematic review and meta-analysis. Int J Cardiol 2013; 167(5):2031–38

4. Al-Ani M, et al: Pericardial mass in a patient with rheumatoid arthritis. BMJ Case Rep 2015; 2015: pii: bcr2015209861

5. Bhat P, et al: Cardiac compression from a rheumatoid pericardial mass. Heart 2006; 92(9): 1337

6. Rodriguez Monserrate CP, et al: Rheumatoid pericardial mass producing right ventricle inflow tract restriction: a case report.Bol Asoc Med PR 2012; 104(4): 47–49

7. Soh MC, et al: Pericardial effusions with tamponade and visceral constriction in patients with rheumatoid arthritis on tumour necrosis factor (TNF)-inhibitor therapy. Int J Rheum Dis 2009; 12(1): 74–77

8. Ozkan H, et al: A rare side effect due to TNF-alpha blocking agent: Acute pleuropericarditis with adalimumab. Case Rep Rheumatol 2013; 985914

9. Edwards MH, Leak AM: Pericardial effusions on anti-TNF therapy for rheumatoid arthritis – a drug side effect or uncontrolled systemic disease? Rheumatology (Oxford) 2009; 48(3): 316–17

10. Lather HD, Kahlenberg JM: Hemorrhagic pericardial effusion with tamponade: a rare adverse effect of infliximab – case report and literature review. Case Rep Rheumatol 2016; 2016: 2576496

11. Lee JL, et al: Biologics and cardiovascular events in inflammatory arthritis: a prospective national cohort study. Arthritis Res Ther 2018;20(1):171

12. Distler JH, et al: The controversial role of tumor necrosis factor alpha in fibrotic diseases. Arthritis Rheum 2008; 58(8): 2228–35

13. Yoshikawa GT, et al: Formation of multiple pulmonary nodules during treatment with leflunomide. J Bras Pneumol 2015; 41(3):281–84