Impact of age and antibody type on progression from single to multiple autoantibodies in type 1 diabetes relatives

Context. Islet autoantibodies are markers of type 1 diabetes and an increase in number of autoantibodies detected during the preclinical phase is predictive of progression to overt disease. Objective. To refine the impact of age in relation to islet antibody type on the progression from single to multiple autoantibodies in relatives of people with type 1 diabetes. Research design and methods. We examined 994 relatives with normal glucose tolerance and positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to GAD (GADA), insulin (IAA), IA-2 (IA-2A), zinc transporter 8 (ZnT8A) and ICA were tested every 6-12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8yr; 8-11yr; 12-17yr; ≥18yr and optimal age breakpoints identified by recursive partitioning analysis.Results. After median follow-up of 2 years, 141 relatives had developed ≥ 1 additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by antibody type: relatives with GADA showed a gradual decrease in risk over the four age groups, while relatives with IAA showed a sharp decrease above the age of 8 years. Recursive partitioning analysis identified age breakpoints at 14 years in relatives with GADA and at 4 years in relatives with IAA. Conclusions. In relatives with IAA, spread of islet autoimmunity is largely limited to early childhood, while immune responses initially directed at GAD can mature over a longer period of time. These differences have important implications for monitoring these subjects and for designing prevention trials.