Hierarchical order of autoantigen spreading and progression to T1D in the TEDDY Study

Background: The first appearing diabetes-associated autoantibody (Ab) has been shown to vary risk of T1D. Here, we assessed risk of autoantigen spreading by appearance of the second-appearing Ab and further progression to T1D in the Environmental Determinants of Diabetes in the Young (TEDDY) study.

Methods: HLA-eligible children were followed for development of primary Abs (GADA, IA-2A and IAA) and progression to T1D. Primary persistent Ab was defined as positive for a specific Ab at two consecutive visits confirmed by two laboratories.  ZnT8A was measured on all children who developed a primary Ab.

Results: There were 633 children who developed a persistent first-appearing Ab (IAA n=260, GADA n=296, or combination of GADA and IAA n=77) with a median of 9 years follow up from birth. GADA or IAA were also more likely to appear as a second appearing Ab. There was no significant difference in the antigen-specific risk of either ZnT8A or IA-2A appearing as a second Ab.In children with IAA as the first appearing, IA-2A (HR 7.7, 95%CI 4-15, p<0.0001) and GADA (HR 2.3, 95%CI 1.2-4.2, p=0.009) as a second-appearing Ab conferred increased risk of progression to T1D as compared with not developing a second Ab; while, ZnT8A did not contribute to risk of progression to T1D (HR 1.4, 95%CI 0.6-3.4, p=0.4).In children who developed GADA as first-appearing, appearance of IA-2A (HR 10.4, 95%CI 4-26, p<0.0001), IAA (HR 5.5, 95%CI 2.3-13.0, p<0.0001) and ZnT8A (HR 2.98, 95%CI 1-8, p=0.03) as a second Ab conferred an increased risk of progression to T1D. Among those with both IAA and GADA, IA-2A as the second Ab conferred a higher risk of progression to T1D compared with ZnT8A (HR 2.4, 95%CI 1.0-5.6, p=0.05).

Conclusion: The hierarchical order of autoantigen spreading augments estimation of the risk of progression to clinical onset of T1D.