Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study

Abstract

Objective: β-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk.

Research design and methods: Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes.

Results: Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years.

Conclusions: Type 1 diabetes risk remained high in children who had developed multiple β-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk.

Figure 1

Flowchart of β-cell autoantibody (Ab) persistent positivity (n = 596), number of autoantibodies at time of initial seroconversion (single autoantibody, n = 500; multiple autoantibodies, n = 96), number that remained positive or became negative, and how many developed type 1 diabetes (T1D).

Figure 2

A: Cumulative incidence of development of multiple autoantibodies (Abs) after initial seroconversion and cumulative incidence of autoantibody reversion. B: Risk of progression to type 1 diabetes by autoantibody persistence (single and multiple) and reversion.