Immunosuppression in Down syndrome regression disorder: a prospective observational cohort study

Abstract Down syndrome regression disorder is a severe neuropsychiatric condition for which intravenous immunoglobulin offers partial benefit in many cases. The efficacy of second-line immunosuppressive therapies in those with partial responses to intravenous immunoglobulin (IVIg) remains unclear. This study sought to evaluate the comparative efficacy of B-cell depletion, Janus kinase inhibition, and mycophenolate mofetil as second-line immunosuppressive therapies in individuals with Down syndrome regression disorder. This multicenter, prospective observational cohort study included 126 individuals with Down syndrome regression disorder. Participants were aged 10–30 years and had demonstrated greater than 50% improvement following IVIg on either the Bush-Francis Catatonia Rating Scale or the Neuropsychiatric Inventory Questionnaire, followed by second-line immunosuppression with one of three agents. Participants received B-cell depletion (rituximab or biosimilar; n=63), Janus kinase inhibitors (tofacitinib or baricitinib; n=34), or mycophenolate mofetil (n=29). Treatments were assigned as part of clinical care and not randomized. The primary outcomes were change scores (Δ) on the Bush-Francis Catatonia Rating Scale and the Neuropsychiatric Inventory Questionnaire following immunosuppression. Secondary outcomes included treatment-emergent adverse event rates. All therapies produced symptomatic improvement; however, mean Δ Bush-Francis Catatonia Rating Scale and Δ Neuropsychiatric Inventory Questionnaire scores were greatest with B-cell depletion (mean [standard deviation] Δ Bush-Francis Catatonia Rating Scale: –9.6 [4.1]; Δ Neuropsychiatric Inventory Questionnaire: –16.5 [6.1]) compared with Janus kinase inhibition (Δ Bush-Francis Catatonia Rating Scale: –6.3 [5.0]; Δ Neuropsychiatric Inventory Questionnaire: –12.0 [7.2]) and mycophenolate mofetil (Δ Bush-Francis Catatonia Rating Scale: –3.0 [4.3]; Δ Neuropsychiatric Inventory Questionnaire: –5.7 [6.8]). One-way ANOVA showed significant between-group differences for both Bush-Francis Catatonia Rating Scale (p < .001) and Neuropsychiatric Inventory Questionnaire (p < .001). Post hoc Tukey tests revealed B-cell depletion to be significantly more effective than mycophenolate mofetil on both outcomes. Adverse event rates were lowest in the B-cell depletion group (2.40 events/patient) compared with Janus kinase inhibition (3.32) and mycophenolate mofetil (4.14) (overall p < .001). In individuals with Down syndrome regression disorder who partially respond to intravenous immunoglobulin, second-line immunosuppression with B-cell depletion was associated with the greatest clinical improvement and the most favorable safety profile.