Systemic Lupus Erythematosus (SLE) presents a complex autoimmune challenge characterized by chronic inflammation and multi-organ involvement. This paper offers a comprehensive analysis of anifrolumab, a promising monoclonal antibody that targets type I interferon signaling, as a potential treatment for SLE. It also compares with existing therapies, namely belimumab and rituximab. Anifrolumab received FDA approval in 2021 based on evidence from clinical trials, such as MUSE and TULIP-2, demonstrating its effectiveness in reducing disease activity, glucocorticoid usage, and flares among SLE patients. However, concerns regarding its safety profile, particularly herpes zoster infections and immunosuppression, should be addressed. Comparative analysis of belimumab and rituximab reveals their distinct mechanisms of action and levels of clinical evidence. Belimumab, focusing on B-cell activity, has a longer history of reducing disease activity and flares. Rituximab, while promising, lacks direct comparative data. Challenges related to the long-term safety and efficacy of anifrolumab emphasize the need for personalized treatment strategies, patient selection, and real-world data integration. The paper discusses the importance of tailoring therapies based on biomarker profiles and clinical characteristics, involving patients in shared decision-making, and monitoring treatment responses over time. The paper highlights ongoing research and clinical trials exploring new therapeutic approaches for SLE, offering hope for improved outcomes. It underscores that anifrolumab, while promising, should be considered within the context of individual patient needs, with further studies necessary to refine treatment choices for SLE patients.