Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

New onset autoimmune diabetes and thyroiditis following a single cycle of ipilimumab/nivolumab for metastatic mesothelioma (#633)

Sophie Templer 1 , Albert Hsieh 1 2 , Holly Murdoch 3 , Marg McGill 2 3 , Stephen Twigg 1 2 , Sarah Parry 1 2
  1. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  2. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  3. Diabetes Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Case: A 71-year-old retired finance worker presented to the Emergency Department with palpitations, weight loss (4kg in four weeks), anorexia, polydipsia and polyuria. He had been diagnosed with mesothelioma 2 years earlier, initially treated with chemo-radiotherapy, and commenced combination ipilimumab/nivolumab four weeks prior to this presentation. Other background included autoimmune hepatitis, renal cell carcinoma, and paroxysmal atrial fibrillation (AF).

Assessment revealed rapid AF, which reverted to sinus rhythm with bisoprolol. TSH was suppressed to 0.01mIU/L (0.27-4.20) with elevated fT4 (37.7pmol/L, 10-20) and fT3 (9.4pmol/L, 3.1-6.8). TPO antibody was elevated, while TSH receptor and thyroglobulin antibodies were negative. Thyroid scintigraphy demonstrated reduced uptake (0.2%, 0.5-3.5) while ultrasound findings were consistent with thyroiditis. Morning cortisol was normal (502nmol/L).

While in Emergency, a random glucose level was 25.2mmol/L. Ketones were elevated to 4.2mmol/L without acidosis. HbA1c was only modestly elevated to 6.3% (45mmol/mol), suggesting rapid onset of hyperglycaemia. Non-fasting C-peptide was relatively low at 249pmol/L (200-1200) with a paired glucose of 26.8mmol/L. Anti-GAD was 85.7U/mL (<1.0), anti-IA2 was undetectable, and anti-ZnT8 was not measured. He was commenced on basal-bolus insulin and discharged home two days later.

The patient became hypothyroid within four weeks of this presentation, requiring levothyroxine replacement. He remains on basal-bolus insulin with continuous glucose monitoring showing a recent glycaemic management index of 8.2%.

Discussion: This is an unusual case of dual grade-3 endocrinopathies occurring after a single cycle of combination PD-1/CTLA-4 immunotherapy. The incidence of autoimmune diabetes in recipients of PD-1/CTLA-4 therapy is <1%1 and the median time to onset after initial checkpoint inhibitor exposure is 12 weeks.2 Type 1 diabetes antibodies are positive in over a third of cases and are often associated with earlier onset and more severe diabetes phenotype.2 The incidence of hyperthyroidism is 4.5% in PD-1/CTLA-4 therapy1 and typical onset is within three weeks of exposure.3

  1. Vardarli, I., Tan, S., Brandenburg, T., Weidemann, F., Görges, R., Herrmann, K., & Führer, D. (2024). Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled Trials. The Journal of Clinical Endocrinology and Metabolism, 109(4), 1132–1144.
  2. Wu, L., Tsang, V., Menzies, A. M., Sasson, S. C., Carlino, M. S., Brown, D. A., Clifton-Bligh, R., & Gunton, J. E. (2023). Risk Factors and Characteristics of Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus (CIADM): A Systematic Review and Delineation From Type 1 Diabetes. Diabetes Care, 46(6), 1292–1299.
  3. Lee, H., Hodi, F. S., Giobbie-Hurder, A., Ott, P. A., Buchbinder, E. I., Haq, R., Tolaney, S., Barroso-Sousa, R., Zhang, K., Donahue, H., Davis, M., Gargano, M. E., Kelley, K. M., Carroll, R. S., Kaiser, U. B., & Min, L. (2017). Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy. Cancer Immunology Research, 5(12), 1133–1140.