Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to understand the timing and factors associated with anti-programmed cell death protein-1 (PD-1)/anti-programmed cell death protein-1 ligand (PD-L1) inhibitor-induced Type 1 diabetes. METHODS: We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t-tests. RESULTS: The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5-448) days with ketoacidosis in 76% of cases. The average ± sd HbA1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes-associated antibodies at presentation, and those with antibodies had a more rapid onset (P=0.005) and higher incidence of diabetic ketoacidosis (P=0.02) compared to people without antibodies. CONCLUSIONS: Many people developed Type 1 diabetes within 3 months of initial PD-1/PD-L1 inhibitor exposure. People presenting with Type 1 diabetes-associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state-of-the-art therapies need to be aware of this potential severe adverse event.

Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. METHODS: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. RESULTS: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders. CONCLUSIONS/INTERPRETATIONS: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378508 FUNDING: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Autoimmune polyendocrine syndrome type 1 (APS-1) as a model for understanding autoimmune polyendocrine syndrome type 2 (APS-2).

Autoimmune polyendocrine syndromes type 1 and 2 (APS-1 and APS-2) are diverse in regards to their component diseases and immunologic features of pathogenesis. Animal models and human studies highlight the importance of alleles of HLA (human leukocyte antigen)-like molecules determining tissue specific targeting that with the loss of tolerance leads to organ specific autoimmunity. Knowledge of the syndromes and component diseases allows clinicians to recognize and prevent illness prior to morbidity. With the current understanding of the syndromes, a paradigm for diagnosis, screening and treatment can be established. Once genetically susceptible individuals are identified screening for autoantibodies can be performed. Amongst autoantibody positive individuals, monitoring for physiologic decompensation, with a goal of treating prior to morbidity and in some cases mortality, follows. With continued basic and clinical research, therapies aimed at treating the underlying autoimmunity and disease prevention should become possible.