Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study

Abstract

Objective: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Research design and methods: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.

Results: There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.

Conclusions: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.

Figure 1

Cumulative incidence in children with distinct single first-appearing autoantibody positivity (IAA or GADA) for progression to distinct single second-appearing autoantibody positivity. A: The cumulative incidence of the second-appearing autoantibody by months since first-appearing IAA. B: The cumulative incidence of the second-appearing autoantibody by months since first-appearing GADA. The lines represent IAA (blue line), GADA (black line), IA-2A (red line), and ZnT8A (green line).

Figure 2

Cumulative incidence in children with a distinct single second-appearing autoantibody for progression to T1D: GADA or IAA (blue line), IA-2A (red line), and ZnT8A (green line). The 5-year (60-month) cumulative risk of T1D among the children who remained single autoantibody positive is shown (black dotted line). The median (IQR) time between the first- and second-appearing autoantibody seroconversions was 5.3 (3.0–13.3) months for GADA or IAA, 6.9 (3.7–17.6) months for IA-2A, and 13.3 (6.3–23.7) months for ZnT8A.