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

Authors

Nicholas L Hartog, Konrad Pisarczyk, Mike Samad, Katerina Vlachopoulou, Amanda Harrington

Published in

Advances in therapy. Oct 26, 2026. Epub Oct 26, 2026.

Abstract

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.

PMID:
42932134
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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