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

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare disease associated with immunodeficiency and immune dysregulation. Management may include sirolimus and immunoglobulin replacement therapy (IRT); neither is specifically approved for APDS in the USA. This systematic literature review evaluated the effectiveness and safety of sirolimus and IRT in patients with APDS. MEDLINE, Embase, and Cochrane Library databases were searched through July 2025, supplemented by grey literature and bibliographic searches. Eligible records reported treatment outcomes in patients with APDS receiving sirolimus and/or IRT. Quality assessment was performed; findings were narratively synthesized. Seventy-nine records (82 publications) were included: 69 case reports of 103 patients, 8 retrospective cohort studies, and 2 case series, describing 136 treatment regimens. No prospective studies were identified. Evidence was dominated by case reports (87.3% of records), assessed as low-to-moderate quality. Most records did not include pre- and post-treatment data, comparators, or clearly defined outcomes. Infections were the most commonly reported outcome (44 records), with improvement reported in 59.5% of patients in cohort studies and in 50.0% of regimens in case reports, although improvement was rarely defined. Lymphoproliferation outcomes (35 records) showed no improvement in 35.7–43.8% of patients in cohort studies and in 50.0% of regimens in case reports, although improvement definitions and pre- and post-treatment data were limited. Progression to hematopoietic stem cell transplantation occurred in 12.9% of patients. In all patients receiving sirolimus in cohort studies, renal/hepatic toxicity was reported in 19.2–25.0% of patients and discontinuation from any cause was reported in 25.0–34.6% of patients. Despite numerous records, the effectiveness of sirolimus and IRT cannot be reliably quantified from the published APDS literature, which largely consists of low-to-moderate quality case reports. More methodologically rigorous studies are needed to inform treatment strategies for these therapies in APDS. Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare disease that affects genes that influence the immune system. Patients with APDS often get infections, lymph nodes or spleen enlargement, and other health problems. The only treatment for APDS approved by the US Food and Drug Administration is leniolisib. Other medicines, such as sirolimus and immunoglobulin replacement therapy (IRT), are also used to manage features of APDS. How well these drugs treat features of APDS such as infections is unclear. We reviewed medical articles to understand how well sirolimus and IRT have been studied in APDS and whether they are safe. We found 79 records about these treatments. Most of these reports included very few patients, often only one. There were no high-quality studies that compared groups of patients or tested treatments in a planned way. In some reports, patients with APDS receiving these treatments had fewer infections or fewer cases of swollen lymph nodes or an enlarged spleen, but the results differed for each patient. Most reports did not compare patients before and after treatment or give clear results, making it difficult to understand whether these treatments provided benefit. Some patients receiving sirolimus had liver or kidney problems, and some patients had to stop taking the medication. Overall, the effectiveness of sirolimus and IRT for APDS cannot be accurately measured from these reports. Higher quality studies are needed to find out whether these treatments help patients with APDS and what risks they might have.