Spondyloenchondrodysplasia (SPENCD) is a rare monogenic interferonopathy caused by biallelic ACP5 mutations, characterized by skeletal dysplasia, neurological involvement and immune dysregulation frequently manifesting as lupus-like disease. Autoimmune cytopenias, particularly autoimmune hemolytic anemia (AIHA), are among the most severe and treatment-refractory manifestations. Anifrolumab, a monoclonal antibody targeting interferon alpha receptor subunit 1 (IFNAR1), blocks signaling by all type I interferons and is approved for moderate-to-severe systemic lupus erythematosus. We report a 50-year-old man with SPENCD-associated lupus and refractory, transfusion-dependent AIHA who achieved sustained hematologic remission following anifrolumab initiation. Using this case as a framework, we discuss the pathophysiological basis of SPENCD, the spectrum and treatment challenges of its associated autoimmune cytopenias, and the evolving role of targeted therapies in monogenic interferonopathies, with particular emphasis on SPENCD, and summarize the published experience with anifrolumab in these disorders. Collectively, this case and the available literature provide preliminary support for IFNAR1 blockade as a mechanism-based, steroid-sparing strategy for refractory autoimmune cytopenias in SPENCD.