A 62-year-old man was admitted to the Emergency Department for dyspnea and chest pain. His medical record was notable for unilateral renal agenesis. He worked as a clerk and did not smoke, drink alcohol, or use illicit drugs. He had neither a family nor a personal history of cancer or autoimmune diseases; however, he reported having been hospitalized twice during the previous year for recurrent pericardial effusions, for which he had been diagnosed with IRP and was receiving treatment with colchicine and NSAIDs.
On examination, blood pressure was 120/60 mmHg, heart rate 96 beats per minute, and respiratory rate 30 breaths per minute, with normal oxygen saturation. Physical examination revealed muffled heart sounds, but no jugular vein distention or paradox pulse. Blood tests revealed mild anemia, mildly elevated troponin levels (43 ng/L, normal values < 14), elevated levels of pro-BNP (3,600 pg/mL, normal values < 227), and strikingly high levels of inflammatory markers C-reactive protein (CRP, 135 mg/L, normal values < 6), erythrocyte sedimentation rate (ESR, 118 mm/1 h, normal values < 20), and ferritin (640 ng/mL, normal values 15-150 ng/mL). A full autoantibody panel, including rheumatoid factor, anti-citrullinated protein antibody, antinuclear antibodies, cryoglobulins, and anti-neutrophil cytoplasmic antibodies, was negative. Electrocardiogram showed diffuse ST-segment elevation. Trans-thoracic echocardiography revealed ubiquitous pericardial effusion, with a maximum thickness of 45 mm. Following ineffective attempts to drain the excess pericardial fluid, a pleuro-pericardial window was surgically created. Pericardial fluid analysis revealed elevated concentrations of lactate dehydrogenase and total protein. A search for cancer cells and Mycobacterium tuberculosis through polymerase chain reaction was negative, as were Gram stain and bacterial culture studies.
Over the following days of hospitalization, dyspnea and chest pain progressively worsened. Repeated echocardiography revealed a closure of the pleuro-pericardial window and relapse of the pericardial effusion, with a maximum thickness of 40 mm. A whole-body contrast-enhanced computed tomography (CT) confirmed pericardial effusion with thickening of the pericardial sheets, while also revealing a pseudo-tumoral infiltration of the right atrium (Figure 1). Moreover, abdominal scans revealed solid tissue surrounding the right kidney and aorta (Figure 2). Together with cardiac involvement, these findings of retroperitoneal involvement with peculiar "coated aorta" and "hairy kidney" radiologic signs pointed at a diagnosis of ECD. Since the skeletal system is almost invariably involved in ECD, a bone scan was then requested, which revealed pathognomonic symmetric radiotracer uptake in the long bones of the lower limbs (Figure 3). A CT-guided biopsy of the perinephric solid tissue was performed. Histology studies identified xanthogranulomatous infiltration with foamy histiocytes staining positive for CD68, but negative for S100 and for CD1a, all findings diagnostic for ECD. Molecular techniques revealed the presence of the BRAFV600E mutation in pathological histiocytes, as described.
Once a diagnosis of ECD was established, a critical problem to be faced was which pharmacological approach to choose following failure of the pleuro-pericardial window. The traditional drug of choice in ECD is IFN-alpha. However, we preferred not to choose IFN-alpha, as previous experience suggests limited efficacy in cases of severe heart inflammation. As a valid alternative, we focused on vemurafenib, a small molecule inhibitor of BRAFV600E, which is highly effective in the treatment of ECD. However, efficacy of vemurafenib is normally observed only after months of treatment, while the pericardial effusion of our patient was quickly worsening and dictating the need for a rapid intervention. The last alternative therapeutic strategy involved the use of anti-cytokine agents. The main anti-cytokine therapies that have been investigated in ECD are (1) anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, (2) infliximab, a TNF-alpha monoclonal chimeric antibody, and (3) tocilizumab, a monoclonal antibody blocking the IL-6 receptor. Between these three drugs we chose anakinra, because of its rapid onset of action, excellent safety profile, and:above all:the demonstrated efficacy in the treatment of idiopathic pericarditis, as well as ECD.
Anakinra was thereby started at a standard daily subcutaneous dose of 100 mg. Already 2 days after initiation of anakinra treatment, laboratory tests showed a steep reduction of ESR and CRP levels (22 mm/1 h and 16 mg/L, respectively), and the patient reported a marked improvement of fatigue and asthenia. In the following days, repeated echocardiography evaluations revealed progressive reabsorption of the pericardial effusion. The patient was thereby discharged and re-evaluated after 2 months of daily anakinra treatment. At this point, inflammatory markers had completely normalized, hemoglobin levels increased, and the patient reported no signs of cardiac failure and a considerable improvement in quality of life. A new echocardiography showed a substantial reduction of pericardial effusion, which had a maximum thickness of 16 mm. Anakinra was maintained as monotherapy, and the patient remained asymptomatic in the absence of disease flares for the following 1 year. Imaging restaging of ECD confirmed improvement of heart involvement and stability of retroperitoneal fibrosis.