Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with rare but severe cardiac manifestations, including myocarditis and pericarditis. The coexistence of SLE with sickle cell trait (SCT), an inherited hemoglobinopathy prevalent among individuals of African descent, is exceptionally rare and presents significant diagnostic challenges due to overlapping clinical features. To describe the case of an Afro-Ecuadorian male with SLE and sickle cell trait who developed an uncommon presentation of myopericarditis and pericardial effusion. A 48-year-old African American male with no prior medical history presented with persistent fever, polyarticular arthralgias, and pleuritic chest pain. Investigations revealed sickle cell trait (SCT) and myopericarditis with pericardial effusion, marking the initial manifestation of SLE. Diagnostic delays occurred due to overlapping symptoms and a family history of sickle cell disease. Laboratory findings showed elevated hemoglobin S (<50%), positive ANA (1:1280, coarse speckled pattern), and anti-Smith/RNP antibodies, meeting EULAR/ACR 2019 criteria for SLE. Cardiac MRI confirmed myopericarditis. Treatment with pulse methylprednisolone, oral prednisone, and mycophenolate mofetil resulted in clinical improvement, with stable disease control on immunomodulatory therapy during follow-up. This case highlights the diagnostic complexity of SLE in patients with SCT, particularly when presenting with myopericarditis as the initial manifestation. It emphasizes the importance of a comprehensive diagnostic approach and timely initiation of immunosuppressive therapy to optimize clinical outcomes. This report broadens the understanding of overlapping syndromes involving SLE and SCT.

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