Efficacy of rituximab in autism spectrum disorders associated with hereditary folate malabsorption with signs of antineuronal autoimmunity

Abstract

Background. One of the key advances in psychiatry is an elucidation of the association of hereditary folate malabsorption (HFM) with autistic spectrum disorders (ASD), the evidence for which is based on the results of 5 meta-analyses of randomized controlled trials. It is shown that in such cases the antineuronal autoimmune reaction is an important mechanism of encephalopathy formation. The purpose of the study was to investigate the efficacy of rituximab in children with HFM-associated ASD who showed serological signs of antineuronal autoimmunity to expand the current arsenal of neuroprotective therapy in immunodependent encephalopathy in such cases. Materials and methods. Medical data of 138 children aged 3 to 8 years with HFM and ASD (97 boys and 41 girls) were analyzed. Parents of 62 of 81 patients with signs of antineuronal autoimmunity agreed to rituximab immunotherapy at a dose of 375 mg/m2 of body surface area per month for 3–9 months (study group, SG). Relatives of the other 19 patients with a similar distribution of antineuronal autoantibodies refused treatment (control group, CG). The dynamics of the mental state of children during immunotherapy was assessed by the ABC scale. For statistical analysis, we calculated the parametric Student’s t-test with the confidence probability p and the non-parametric criterion — the number of signs Z by U.V. Urbach, as well as the odds ratio (OR) and 95% confidence interval (95% CI). Results. Rituximab treatment resulted in a progressive decrease in serum antineuronal autoantibodies concentration in patients with ASD associated with HFM, with a more pronounced effect in the production of autoantibodies to neuronal potassium channels compared to autoantibodies to the GADA with complete elimination of the seropositivity after a 9-month course of immunotherapy in 92 % of cases. The phenomenon of rituximab-induced elimination of serum antineuronal autoantibodies is associated with the effect of neuroprotection, which was confirmed by the normalization of previously elevated serum concentrations of laboratory biomarkers of NSE cerebral damage (OR = 17.875; 95% CI = 4.738–67.436 at Ab to GADA and 41.800; 7.257–240.778 at Ab to potassium channels) and S-100 protein (9.750; 2.707–35.113 and 18.333; 3.462–97.083, respectively). In parallel, there was a progressive improvement in all indicators of the mental status of children with ASD on the ABC scale with a latency period of about 2 months (p < 0.05: Z < Z0.05). Conclusions. Immunotherapy with rituximab by eliminating the serological signs of antineuronal autoimmunity realizes the effect of neuroprotection, reducing the severity of all major clinical signs of ASD in children with HFM.