Immunosuppressive Therapies in Down Syndrome Regression Disorder: A Prospective Observational Cohort Study
Jonathan Santoro1, Lilia Kazerooni2, Maeve Lucas2, Mariam Yousuf2, Samuel Otey2, Lina Nguyen2, Nidhiben Anadani3, Melanie Manning4, Angela Rachubinski5, Ryan Kammeyer6, Noemi Spinazzi7, Catherine Franklin8, Eileen Quinn9, Joaquin Espinosa5, Michael Rafii10
1Department of Neurology, Children's Hospital Los Angeles, 2Children's Hospital Los Angeles, 3University Of Oklahoma Health Science Center, 4Stanford School of Medicine, 5Linda Crnic Institute for Down Syndrome, 6Childrens Hospital Colorado, 7University of California San Francisco, 8The University of Queensland, 9University of Toledo, 10USC Alzheimer'S Therapeutic Research Institute
Objective:
This study aimed to evaluate the efficacy of immunosuppressive therapies in individuals with DSRD who were partial responders to IVIg.
Background:
Down Syndrome Regression Disorder (DSRD) is a neuropsychiatric condition characterized by acute or subacute cognitive and functional decline in individuals with Down syndrome. This condition occurs in the 2nd and 3rd decades of life and can be devastating for individuals and caregivers. Intravenous immunoglobulin (IVIg) has shown therapeutic benefit in most cases, however, some individuals demonstrate only partial responses.
Design/Methods:
In this prospective, observational, non-randomized study, individuals with DSRD who demonstrated over 50% improvement on the Bush-Francis Catatonia Rating Scale (BFCRS) or Neuropsychiatric Inventory Questionnaire (NPI-Q) following IVIg were enrolled. Participants subsequently received one of three immunosuppressive regimens: B-cell depletion (rituximab or biosimilar), Janus kinase (JAK) inhibitors, or mycophenolate mofetil (MMF). Outcomes were assessed across three timepoints: baseline, post-IVIg, and post-immunosuppression.
Results:
Among 126 individuals, B-cell depletion (n=63), JAK inhibition (n=34), and MMF (n=29) were administered. All treatments produced improvement on BFCRS and NPI-Q scores. B-cell depletion yielded the most benefit (BFCRS: 4.2 ± 1.1; NPI-Q: 5.1 ± 1.3), followed by JAK inhibition (BFCRS: 7.6 ± 1.4; NPI-Q: 8.8 ± 1.5), with MMF being the least effective (BFCRS: 11.3 ± 1.6; NPI-Q: 13.9 ± 1.9). ANOVA revealed significant group differences on BFCRS and NPI-Q scores (p < 0.001) between B-cell depletion and MMF and JAK inhibitors and MMF. Abnormal lumbar puncture findings predicted response to B-cell depletion (OR: 8.66, p < 0.001), and abnormal MRI predicted response to JAK inhibition (OR: 3.98, p < 0.001).
Conclusions:
Immunosuppressive therapy may offer additional benefit in individuals with DSRD who partially respond to IVIg. Neurodiagnostic abnormalities may guide treatment selection. These findings support the need for randomized trials evaluating precision-based immunotherapy in DSRD.
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