Use of Sirolimus and Immunoglobulin Replacement Therapy (IRT) in Patients with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS): A Systematic Literature Review (SLR)

Introduction Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), a rare inborn error of immunity, is associated with immunodeficiency and immune dysregulation. Clinical management includes symptomatic treatment with immunoglobulin replacement therapy (IRT) and sirolimus, neither of which is approved by the U.S. Food and Drug Administration for the treatment of APDS. This systematic literature review (SLR) aimed to evaluate the effectiveness of IRT and/or sirolimus in patients with APDS. Methods An SLR was conducted to assess the evidence base and quality of literature specific to the impact of IRT and/or sirolimus on clinical outcomes in APDS, including manifestations, treatment utilization, and mortality. Searches were conducted in MEDLINE, Embase, and the Cochrane Library databases from database inception to July 2025. Grey literature searches included relevant conference proceedings and clinical trial registries; bibliography reviews were hand searched. Eligible publications included patients with clinically or genetically confirmed APDS; study types included clinical trials, observational studies, case series or reports, chart reviews, and real-world database analyses reporting IRT or sirolimus/rapamycin treatment outcomes. Publication quality assessment was performed using standard tools. Results Of the 79 studies identified, 90% (n = 71) were single-patient case reports (69 [87%]) or small (≤6 patients) case series (2 [3%]); 10% (n = 8) were retrospective cohorts. No prospective or controlled trials were available, and outcomes were inconsistently defined and quantified. Conclusion Quality evidence supporting the effectiveness of IRT and/or sirolimus in APDS is limited, with 90% of the data derived from case reports or case series involving ≤6 patients. These results highlight the need for quality prospective studies evaluating the effectiveness of these agents, specifically in APDS.