Immune dysregulation and autoimmune lymphoproliferative syndrome (ALPS)-like phenotypes in childhood-onset Sjögren’s disease: clinical, immunological, and therapeutic implications

Childhood-onset Sjögren’s disease (cSjD) is a rare autoimmune disorder with heterogeneous clinical manifestations. Beyond recurrent parotitis and sicca symptoms, systemic features such as cytopenias and lymphoproliferation are frequently observed, raising diagnostic concerns for autoimmune lymphoproliferative syndrome (ALPS) or ALPS-like immune dysregulation. This study assessed clinical, immunological, and molecular features of immune dysregulation in cSjD and explored potential therapeutic implications. Consecutive cSjD patients enrolled at Gaslini Children’s Hospital, Genoa, Italy, between May 2023 and February 2024 underwent clinical and ultrasonographic evaluation for lymphoproliferative manifestations. Laboratory investigations included full blood count, immunoglobulins and IgG subclasses, vitamin B12, lymphocyte subsets including double-negative T cells, IL-10, IL-18, soluble FAS ligand (sFASL), and FAS-mediated lymphocyte apoptosis. Targeted next-generation sequencing of 160 genes implicated in haematological and immunological disorders was also performed. Systemic disease activity was assessed using the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). Twenty-one patients with cSjD were included (95% female; median age 14.8 years, interquartile range 12.2–18.8). Eight patients (38%) fulfilled criteria for an ALPS-like phenotype. Compared with children without an ALPS-like phenotype, these patients more frequently had lymphadenopathy (62% vs 8%, p = 0.014) and cytopenia (62% vs 8%, p = 0.014), had higher gamma-globulin levels (2404 ± 716 vs 1533 ± 525 mg/dL, p = 0.006), and were more frequently positive for anti-SSB/La antibodies (87% vs 38%, p = 0.017). Four patients with an ALPS-like phenotype received sirolimus, with an overall reduction in median ESSDAI during follow-up. cSjD is associated with immune dysregulation resembling ALPS in approximately one-third of patients. These findings underscore the importance of comprehensive immunological evaluation in cSjD and suggest immune regulatory pathways as potential targets for tailored therapeutic intervention.