Table 3 Autoantibody (Aab) features characterize heterogeneity in responses to disease-modifying therapy

From: Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review

Study	n	Age group	Population studied^a	Aab feature assessed	Age impact?	Aab methods	Findings
Christie 2002⁵⁹^a	97	Pediatric and adult	• New onset	• Aab type	No	• RBA • Combined autoantibody workshop	• Cyclosporin had no significant effect on frequency of IA-2A+. • In IA-2A− participants Cyclosporin reduced insulin doses and increased C-peptide. • IA-2A+, GADA− participants were most resistant to cyclosporin. • No differential effects were observed for partitioning by ICA+ or IAA+.
Gale 2004 (ENDIT)⁹³^a	552	Pediatric and adult	• FDR (ICA+)	• Aab number • Aab type	No	• Methods not described • Combined autoantibody workshop	• No difference in time to T1D noted between nicotinamide and placebo groups when adjusted for Aab number. • No evidence of a nicotinamide treatment effect in groups divided by Aab status.
Skyler 2005 (DPT-1)⁹⁴^a	372	Pediatric and adult	• FDR • Single Aab+ • Multiple Aab+	• Aab titer • Aab type	Not available	• IIA; RIA • Standardization program not described	• Oral insulin did not delay or prevent T1D progression in ICA+ and IAA+ relatives.
Näntö-Salonen 2008⁹⁵^a	264	Pediatric	• High genetic risk • FDR • Multiple Aab+	• Aab number • Aab titer • Aab type	No	• IIA; RBA • DASP	• Aab features did not impact ability of nasal insulin to delay or prevent T1D.
Pescovitz 2009 (TrialNet)⁶¹^a	87	Pediatric and adult	• New onset	• Aab number • Aab titer • Aab type	No	• IIA: RBA • Standardization program not described	• No significant differential treatment effect of rituximab among subgroups based on Aab+.
Wherrett 2011 (TrialNet)⁵⁷^a	145	Pediatric and adult	• New onset (GAD+)	Aab type	No	• IIA; RBA • Standardization program not described	• Subcutaneous GAD-alum did not preserve insulin secretion in GADA+ participants with recently diagnosed T1D.
Yu 2011 (TrialNet)⁶²	87	Pediatric and adult	• New onset	• Aab number • Aab titer • Aab type	Not available	• RIA • DASP	• Rituximab led to marked suppression of IAA for 1–3 years compared with placebo but had smaller effect on GADA, IA-2A, and ZnT8A. • 40% of IAA+ individuals became IAA- with rituximab (vs. none with placebo). • IAA levels lower for those who maintained C-peptide during 1st year after diagnosis independent of rituximab treatment.
Ludvigsson 2012 (Diamyd)⁵⁸^a	334	Pediatric and adult	• New onset	• Aab titer • Aab type	No	• ELISA • Standardization program not described	• In GADA+ new onset T1D, alum-formulated GAD65 treatment did not reduce loss of stimulated C-peptide vs. placebo. • Stratification based on baseline GADA titer did not impact treatment response.
Herold 2013 (ITN-AbATE)⁹⁶	77	Pediatric and adult	• New onset	• Aab type	No	• IIA; RIA • Standardization program not described	• Significant reduction in ZnT8A titer (but not IA-2A, IAA, or GADA) in teplizumab-treated participants after 1 year but not after 2 years. • Baseline individual Aab positivity did not predict response to teplizumab.
Aronson 2014 (DEFEND-1)⁹⁷	272	Pediatric and adult	• New onset	• Aab number • Aab type	No	• Methods and standardization program not described	• No impact of GADA+ or IA-2A+ or Aab number on Otelixizumab treatment effect.
Demeester 2015⁹⁸	80	Pediatric and adult	• New onset	• Aab number • Aab type	No	• RBA • Immunology of Diabetes Workshop on Insulin Aabs	• Higher IAA levels associated with better preservation of beta cell function and lower insulin with anti-CD3 treatment. • In multivariate analysis, IAA or the interaction of IAA and C-peptide independently predicted outcome together with treatment. • During follow-up, anti-CD3 responders (i.e., IAA+ participants with preserved beta cell function) showed a less pronounced insulin-induced rise in IAA and lower insulin needs. • GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3, and their changes showed no relationship with outcomes.
Krischer 2017 (TrialNet)⁹⁹	560	Pediatric and adult	• FDR • Second degree relative • Multiple Aab+ • Other: third degree relative	• Aab number • Aab titer • Aab type	Not available	• IIA; RIA; microinsulin Aab assay • Standardization program not described	• Among multiple Aab+ relatives with a high IAA titer, 7.5 mg/day oral insulin did not delay or prevent T1D development vs. placebo.
Herold 2019 (TrialNet)⁶⁰	76	Pediatric and adult	• Multiple Aab+	• Aab type	No	• IIA; RBA • Standardization program not described	• Response to teplizumab vs. placebo was greater if ZnT8A+, also if GADA+, or IAA+, and if IA-2A or IAA were negative.

Methods and standardization program were listed as not described for studies either making no mention of methods or program participation or for studies that included a reference in the “Methods” section but did not specifically list the method or specifically mention standardization program participation.
Aab autoantibody, AbATE Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes, ENDIT European Nicotinamide Diabetes Intervention Trial, DEFEND-1 Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes, DPT-1 Diabetes Prevention Trial Type 1, FDR first degree relative, GAD glutamic acid decarboxylase antibody, IA-2 islet antigen-2 antibody, IAA insulin autoantibody, ICA islet cell autoantibody, ITN Immune Tolerance Network, ZnT8 zinc transporter antibody, ELISA enzyme linked immunosorbent assay, IIA indirect immunofluorescence, RIA radioimmunoassay, RBA radiobinding assay, IASP islet autoantibody standardization program, DASP diabetes autoantibody standardization program.
^aParticipant groups were considered new onset if they were within 12 months of T1D diagnosis.

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Table 3 Autoantibody (Aab) features characterize heterogeneity in responses to disease-modifying therapy

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