Sirolimus and Antibody Replacement Fall Short of Proof in Rare Immune Syndrome Review

A sweeping systematic review of the medical literature has concluded that two of the most widely used treatments for activated phosphoinositide 3-kinase delta syndrome, or APDS, have never been tested in a prospective clinical trial for this condition, and that the published evidence supporting them is too weak to quantify how well they actually work. The review, published in Advances in Therapy, examined decades of reports on sirolimus, an immunosuppressive drug, and immunoglobulin replacement therapy, a supportive antibody treatment, in patients with this ultra-rare inborn error of immunity. Despite identifying 79 records describing 136 treatment regimens, the authors found that the evidence base consists almost entirely of low-to-moderate quality case reports, leaving clinicians without reliable estimates of benefit or risk.

APDS is caused by genetic variants that hyperactivate a signaling enzyme called phosphoinositide 3-kinase delta, which is critical to B and T lymphocyte function. Type 1 disease arises from gain-of-function variants in the PIK3CD gene, while type 2 stems from loss-of-function variants in PIK3R1. Both forms are usually inherited in an autosomal-dominant pattern, though de novo variants also occur. The resulting immune dysregulation drives recurrent infections, enlargement of lymph nodes, spleen and liver, autoimmune cytopenias, gastrointestinal inflammation, and an elevated risk of lymphoma. Because the hyperactive enzyme also ramps up signaling through mechanistic target of rapamycin, or mTOR, sirolimus, which inhibits mTOR downstream of PI3K delta, has a plausible biological rationale. Immunoglobulin replacement therapy, meanwhile, corrects the antibody deficiency that underlies much of the infection burden.

Neither drug is specifically approved for APDS in the United States. The only FDA-approved therapy for the syndrome is leniolisib, a targeted PI3K delta inhibitor approved in 2023 for patients aged 12 years and older, which has since gained approvals in the European Union, the United Kingdom, Australia, Israel, Japan, Canada and South Korea. Immunoglobulin replacement therapy does carry FDA approval for primary humoral immunodeficiency more broadly, and current inborn errors of immunity practice parameters recommend it for patients with immunoglobulin G antibody deficiency. But APDS-specific guidance on how sirolimus, immunoglobulin replacement and leniolisib should be sequenced or combined remains limited, which is precisely the gap the review set out to map.

The review followed Cochrane Handbook principles and the PRISMA 2020 reporting standard, with searches of MEDLINE, Embase and the Cochrane Library run from database inception through July 2025, supplemented by grey literature and hand-searched bibliographies. An original search in November 2021 was updated in May 2023, November 2024 and July 2025. After screening 188 full-text records and excluding 106, the team led by Nicholas L. Hartog included 79 reports corresponding to 82 publications. The composition was striking: 69 records, or 87.3 percent, were case reports describing 103 patients; eight were retrospective cohort studies; and two were case series. No prospective or randomized studies were identified at all.

Quality assessment underscored the problem. Using the Newcastle-Ottawa Scale for cohorts and Joanna Briggs Institute checklists for case reports and series, the reviewers judged 62.5 percent of cohort studies to be low quality, both case series to be low quality, and 62.3 percent of case reports to be low or moderate quality. More than a third of records were conference abstracts that could not be formally appraised because they lacked methodological detail. Only 30 percent of cohort and case series studies and 24.6 percent of case reports included pre- and post-treatment data. Just three cohort or case series studies compared treatments against any comparator, all with unadjusted analyses, and only 11.6 percent of case reports clearly defined all clinical outcomes with prespecified, objective criteria.

Infections were the most commonly reported outcome, appearing in 44 records. In cohort and case series studies, improvement of infections was reported in 59.5 percent of patients, though improvement was rarely defined and most studies lacked baseline data. In a case series of six patients on immunoglobulin monotherapy for one year, two experienced a substantial reduction in respiratory tract infections. A cohort of 36 patients on immunoglobulin monotherapy or combination therapy reported partial relief of infectious complications in 63.9 percent, but partial relief was never defined. Across 56 case report regimens, improvement was reported in 50 percent, resolution in 17.9 percent, and no improvement in 32.1 percent. Notably, most instances of improvement occurred when immunoglobulin or sirolimus was combined with antimicrobial prophylaxis, complicating any attribution to the study treatment alone.

Lymphoproliferation outcomes, covering lymphadenopathy, splenomegaly and hepatomegaly, appeared in 35 records and told a more sobering story. In cohort studies of sirolimus, no improvement was reported in 35.7 to 43.8 percent of patients, and in case report regimens, no improvement was reported in half. Lymphadenopathy data from 36 case report regimens showed no improvement in 50 percent, with sirolimus-based regimens improving in 60 to 75 percent of regimens while immunoglobulin-based regimens improved in only 14.3 to 40 percent. Bronchiectasis fared worst of all: in case reports, it failed to improve in 80 percent of the ten regimens reporting it, with no cases of complete resolution. Progression to hematopoietic stem cell transplantation occurred in 12.9 percent of patients overall, with indications including refractory lymphoproliferation and infections compromising quality of life.

Autoimmune manifestations showed similarly inconsistent results. In cohort studies of sirolimus, no improvement in autoimmune cytopenia ranged from 11.1 to 50 percent of patients depending on the study, with resolution reported in 40 to 55.6 percent in two cohorts, and reoccurrence after an initial response reported in a third of case report regimens. For autoimmune gastrointestinal disease, no improvement was reported in roughly half to 54 percent of patients across two cohorts, and one case report documented Crohn disease developing despite ongoing immunoglobulin combination therapy. Biomarker data were sparse: after a median of three years of sirolimus, immunoglobulin G remained outside the normal range in 56.3 percent of one cohort and immunoglobulin M was elevated in 87.5 percent, while across case reports, normalization of immunoglobulin G and M levels occurred in only 26.7 and 30.8 percent of regimens respectively, and neither monotherapy normalized immunoglobulin levels in any reported case.

Safety findings added further caution. In the two cohort studies with available safety data, renal or hepatic toxicity attributed to sirolimus was reported in 19.2 to 25.0 percent of patients. In the largest cohort, sirolimus was interrupted in 19.2 percent and discontinued in 34.6 percent of patients, with reasons ranging from lack of effectiveness and severe headache to renal toxicity. Across case reports, treatment discontinuation or interruption was reported in 8.1 percent of the 124 regimens, driven by increased infection susceptibility, severe aphthous stomatitis, hypertension and neutropenia. Mortality was reported in 12.5 to 13.9 percent of patients in two cohort studies and in 5.8 percent of case report patients, with causes including respiratory failure, cardiac arrest and cancer-related death.

The authors are explicit that the proportions they report describe the distribution of outcomes within the available literature and cannot be interpreted as estimates of treatment effectiveness. Confounding is pervasive: 75 percent of immunoglobulin combination regimens included antibiotic prophylaxis, and 87.5 percent of sirolimus combination regimens included immunoglobulin replacement, making it impossible to isolate any single drug’s contribution. Publication bias likely favors unusual or favorable cases, and overlapping patients across sequential regimens cannot be fully excluded. The reviewers also note that these therapies entered APDS practice before the syndrome’s molecular characterization in 2013, extrapolated from broader primary immunodeficiency populations such as common variable immunodeficiency, and that sirolimus’s systemic mTOR inhibition is not specific to the underlying defect, which may explain both its variable effects and its toxicities.

The contrast with leniolisib is instructive. In a phase 3 randomized trial, leniolisib met its coprimary endpoints, showing significant reductions in index lymph node size and significant increases in the percentage of naive B cells over 12 weeks, with benefits extending up to six years in an open-label extension and generally good tolerability. Yet targeted therapy does not end the need for individualized care: lymphoma affected roughly 12 percent of patients in a systematic review of 351 APDS patients, Hodgkin lymphoma has been reported even in a patient taking leniolisib, and no patient-reported quality of life measures were identified for sirolimus or immunoglobulin replacement anywhere in the reviewed literature. The review’s bottom line is that despite a substantial body of published records, the effectiveness of these two longstanding therapies in APDS cannot be reliably quantified, and methodologically rigorous, systematically collected studies are needed before treatment decisions can rest on solid ground.

Subject of Research: Evidence quality of sirolimus and immunoglobulin replacement therapy in activated phosphoinositide 3-kinase delta syndrome

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

Article References: Hartog, N. L., Pisarczyk, K., Samad, M., Vlachopoulou, K., & Harrington, A. (2026). Sirolimus and Immunoglobulin Replacement Therapy in Patients with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS): A Systematic Literature Review. Advances in Therapy. https://doi.org/10.1007/s12325-026-03833-8

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03833-8

Keywords: APDS, sirolimus, immunoglobulin replacement therapy, systematic review, primary immunodeficiency, leniolisib, PI3K delta, mTOR inhibitor, case reports, lymphoproliferation, inborn errors of immunity, rare disease