Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency

Background Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency (LRBA-/-) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4+/-) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown. Objective To determine the comparative efficacy and long-term outcome of therapy with immunosuppressants (ISs), CTLA4-Ig (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country, multicenter cohort of 98 patients with a 5-year median follow-up. Methods 63 LRBA-/- and 35 CTLA4+/- patients were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies. Results LRBA-/- patients exhibited a more severe disease course than CTLA4+/- patients, requiring more ISs, abatacept, and HSCT to control symptoms. In 58 patients who received abatacept either as a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received ISs as primary therapy (n=61) showed either partial or no disease control (72.1%), necessitating additional ISs, abatacept, or transplantation. Patients with partial or no response to abatacept (n=12) had longer disease activity prior to abatacept therapy with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA-/- patients; 9 (64.2%) showed complete remission, and 3 (21.3%) continued to receive IS after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival. Conclusions Abatacept is superior to ISs in controlling disease manifestations long-term, especially when started early, and may provide a safe and effective therapeutic alternative to transplantation.