Childhood Sjögren’s disease shows ALPS-like immune dysregulation in a third of young patients

A study conducted at Gaslini Children's Hospital in Genoa, Italy, found that eight of 21 children and adolescents with the disorder (38%) fulfilled criteria for an ALPS-like immune dysregulation phenotype. The findings, published in Arthritis Research & Therapy, underscore the importance of comprehensive immunological evaluation in childhood-onset Sjögren's disease and suggest immune regulatory pathways as potential targets for tailored therapeutic intervention.

The research team enrolled consecutive patients with childhood-onset Sjögren’s disease between May 2023 and February 2024, subjecting each to clinical and ultrasonographic evaluation for lymphoproliferative manifestations. Beyond standard assessment, the investigators measured a battery of immunological parameters: full blood counts, immunoglobulins and their subclasses, vitamin B12, lymphocyte subsets including double-negative T cells, the signalling molecules IL-10 and IL-18, soluble FAS ligand, and the capacity of lymphocytes to undergo FAS-mediated apoptosis. Targeted next-generation sequencing covering 160 genes implicated in haematological and immunological disorders was also performed. Disease activity was quantified using the EULAR Sjögren’s Syndrome Disease Activity Index, or ESSDAI.

Twenty-one patients were included in the analysis, 95 percent of whom were female, with a median age of 14.8 years and an interquartile range spanning 12.2 to 18.8 years. Eight patients, representing 38 percent of the cohort, fulfilled criteria for an ALPS-like phenotype.

The clinical and laboratory contrasts between the two groups were pronounced. Children with the ALPS-like phenotype more frequently exhibited lymphadenopathy, at 62 percent compared with 8 percent in those without, a difference that reached statistical significance at p = 0.014. Cytopenia followed an identical distribution: 62 percent versus 8 percent, also at p = 0.014. Gamma-globulin levels were substantially elevated in the ALPS-like group, averaging 2404 ± 716 mg/dL against 1533 ± 525 mg/dL in the comparison group, a difference significant at p = 0.006. Anti-SSB/La antibodies were present in 87 percent of the ALPS-like subgroup versus 38 percent of the remainder, significant at p = 0.017.

Therapeutically, the study offers a preliminary but notable observation. Four patients with the ALPS-like phenotype received sirolimus. During follow-up, these patients showed an overall reduction in median ESSDAI scores, indicating a decrease in systemic disease activity. The authors suggest that immune regulatory pathways may serve as potential targets for tailored therapeutic intervention.

The implications extend beyond treatment selection. Because cytopenias and lymphoproliferation in childhood-onset Sjögren’s disease can raise diagnostic concern for ALPS or ALPS-like immune dysregulation, the study underscores the value of comprehensive immunological evaluation at initial presentation.

Several limitations temper the strength of these conclusions. The cohort is small and drawn from a single centre, and the sirolimus observation involves only four patients without a control group. The study was published as an accepted manuscript shared ahead of final version-of-record edits, meaning some details may be revised. Nonetheless, the study concludes that cSjD is associated with immune dysregulation resembling ALPS in approximately one-third of patients, underscoring the importance of comprehensive immunological evaluation.

The authors conclude that these findings underscore the importance of comprehensive immunological evaluation in cSjD and suggest immune regulatory pathways as potential targets for tailored therapeutic intervention.

Subject of Research: Immune dysregulation resembling autoimmune lymphoproliferative syndrome in childhood-onset Sjögren’s disease

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

Article References: Ancona, S., Palmisani, E., Agrusti, A., Matucci-Cerinic, C., Maronese, N., Dell’Orso, G., Giarratana, M. C., Lanciotti, M., Lupia, M., Caorsi, R., Gattorno, M., Miano, M., & Malattia, C. (2026). Immune dysregulation and autoimmune lymphoproliferative syndrome (ALPS)-like phenotypes in childhood-onset Sjögren’s disease: clinical, immunological, and therapeutic implications. Arthritis Research & Therapy. https://doi.org/10.1186/s13075-026-03920-9

Image Credits: AI Generated

DOI: 10.1186/s13075-026-03920-9

Keywords: childhood-onset Sjögren’s disease, autoimmune lymphoproliferative syndrome, ALPS-like phenotype, immune dysregulation, double-negative T cells, FAS-mediated apoptosis, sirolimus, cytopenia, lymphadenopathy, gamma-globulins, anti-SSB/La antibodies, ESSDAI