Background: Pericardial disease is an uncommon early manifestation of autoimmune diseases, particularly in limited systemic sclerosis (CREST syndrome). Recognizing it as a presenting feature is essential, as it may precede hallmark features of systemic manifestations and require prompt immunosuppressive therapy. Furthermore, serum mucin biomarkers like CA-125, traditionally used in oncology, have emerged as potential indicators of autoimmune serositis; however, their role remains under investigation.

Case Presentation: We describe the case of a 60-year-old woman who presented with dyspnea, peripheral edema, and imaging-confirmed pericardial effusion. Further work-up revealed clinical and immunological features of limited systemic sclerosis (CREST), including positive antinuclear antibodies with a centromere pattern and high titers of anti-centromere antibodies. During hospitalization, she developed cardiac tamponade requiring pericardiocentesis. Notably, CA-125 levels were markedly elevated during active pericardial inflammation. The patient responded favorably to immunosuppressive therapy, which included glucocorticoids and cyclophosphamide. We additionally conducted a narrative review on pericardial involvement in autoimmune diseases, with particular emphasis on systemic sclerosis (SSc). The review includes an epidemiological perspective from the Colombian population, highlighting the local prevalence and clinical implications of these presentations in low-prevalence settings. In addition, we discuss the potential role of mucin-derived biomarkers, especially CA-125, as indicators of active serosal inflammation in systemic autoimmune diseases.

Conclusions: Pericardial effusion can be a heralding sign of systemic sclerosis and may precede classic cutaneous and vascular features. This case underscores the importance of early recognition of autoimmune pericarditis and suggests that CA-125 may serve as a surrogate marker of serosal activity in autoimmune disorders. Clinicians should maintain a high index of suspicion for autoimmune causes in unexplained pericardial disease, and further studies are needed to validate mucin-based biomarkers as diagnostic and prognostic tools.