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Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous manifestations. Biologics such as Belimumab, Anifrolumab, and Rituximab expand treatment options, but real-world comparisons are scarce. We aimed to assess patient profiles, clinical phenotypes guiding therapy, drug survival, and serologic outcomes over 12 months.Methods We performed a retrospective study of SLE patients fulfilling 2019 ACR/EULAR criteria who received Belimumab, Anifrolumab, or Rituximab between 2010 and 2025 at a university hospital. Baseline demographics, clinical manifestations, and laboratory parameters (anti-dsDNA, C3, C4, hemoglobin, leukocytes, lymphocytes, platelets, creatinine, eGFR) were collected. Group comparisons used Kruskal–Wallis and chi-square tests, while longitudinal biomarker changes, causes of discontinuation, and drug survival (Kaplan–Meier) were analyzed.Results We included 84 SLE patients, of whom 76 (90.5%) were female, with a mean age at diagnosis of 35.1 years and mean current age of 45.3 years. Biologic therapies consisted of Belimumab in 47 patients (56.0%), Anifrolumab in 26 (31.0%), and Rituximab in 11 (13.1%).The most common were articular, hematologic, and cutaneous, reflecting the systemic nature of the disease. By treatment, Belimumab was more frequent in renal involvement, Anifrolumab in cutaneous and articular disease, and Rituximab in severe hematologic&neuorpsychiatric manifestations, supporting phenotype-driven selection in clinical practice.Discontinuations occurred mainly due to infections or lack of efficacy, with fewer cases of death or allergic reactions. Kaplan–Meier analysis demonstrated similar 12-month persistence across therapies, although Belimumab showed slightly higher survival rates.Serologic outcomes: At baseline, many patients had elevated anti-dsDNA titers and low complement. Over 12 months, Anifrolumab achieved the fastest C3 recovery, Belimumab induced a sustained anti-dsDNA decline, and Rituximab showed less consistent improvement. Hematologic values (hemoglobin, lymphocytes, platelets) remained generally stable across all groups. Together, these data highlight distinct response profiles that may inform individualized treatment strategies.Abstract PO:05:134 Figure 1Conclusions In this real-world SLE cohort, biologic persistence was comparable, with most discontinuations due to infections or inefficacy. Treatment choice reflected phenotype—Belimumab in renal disease, Anifrolumab in cutaneous/articular, and Rituximab in severe hematologic/neuropsychiatric cases—while serologic responses diverged: Anifrolumab improved C3, Belimumab reduced anti-dsDNA, and Rituximab was less consistent. These findings highlight the need to tailor biologic therapy according to patient profile and serologic trajectory.