New Onset Autoimmune Diabetes Mellitus, Autoimmune Thyroiditis and Subsequent Autoimmune Hepatitis With Monoclonal Antibody to Programmed Cell Death-1 (PD-1) Protein Therapy in a Patient With Non Small Cell Lung Cancer: 18 Months Follow up Experience

Background: Monoclonal antibody to Programmed cell death-1 (PD-1) protein binds to PD-1 receptor and blocks its interaction with PD Ligand 1 and PD Ligand 2, which helps restore the immune response for various types of cancer treatment are used widely. These agents are associated with many auto immune diseases. We describe a case where a patient treated with PD-1 inhibitor manifested three autoimmune diseases. Clinical Case: A 62 year old female with past medical history of Non small cell adenocarcinoma stage IV with gluteal muscle metastasis was referred to endocrinology for new onset Diabetes Mellitus (DM). Family history was negative for thyroid and other autoimmune diseases, Her brother had type 2 DM. On physical examination: elderly female, thin built, BMI: 16.7 kg/m(2) with a non-palpable thyroid and no skin lesions. Patient was started on Pembrolizumab every 3 weeks. During 2nd cycle, her basic metabolic panel revealed blood glucose level of 409 mg/dl, negative serum ketone, normal anion gap of 11 and HbA1c: 7.0 %, Anti TPO: positive; 9 (ref<9 IU/mL) with normal TSH, Ft4 and T3 level. C-peptide level was <0.1 (ref: 0.8- 3.85); Glutamic acid (GAD) antibody elevated: >250 (ref range<5), and Islet Cell Antibody was negative. CT scan of abdomen with contrast showed pancreas within normal limit. Prior to initiation of Pembrolizumab therapy her HbA1C was 5.3 and 8 am serum cortisol level was 19 ug/dl. She was started on multiple dose of subcutaneous insulin therapy for autoimmune DM. Her DM was well controlled on .77 units/ kg insulin dosage targeting a finger stick of 140–200 mg%. Following 16 cycles of Pembrolizumab patient was found to have elevated liver enzymes ALT 807 U/L, AST 1109 U/L, total bilirubin 2.1 mg/dL, with concerns for autoimmune hepatitis. A CT scan with contrast ruled out any metastatic lesion to liver, follow up labs with HbA1c 12.3%, TSH 1.09 uIU/mL, C-peptide remains<0.01 and TPO Ab remains positive: 60 IU/mL. Patient’s HLA pattern was heterozygous DR4-DQ8 and heterogyzous DR1-DQ5 haplotype. Conclusion: The loss of β cell function in our case appeared to be fulminant as suggested by the relatively low glycated hemoglobin level while C-peptide level was undetectable at diagnosis of autoimmune DM. High dose steroid therapy was not successful in reversing the condition and another case reported beta cell destruction was halted by stopping the check point inhibitor therapy. Recently, American society of Oncology article suggested measuring glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 3–6 weeks thereafter risk factors for each subtype of DM to be assessed[1]. Reference: 1. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline, Journal of Clinical Oncology 2018 36:17, 1714–1768, DOI: 10.1200/JCO.2017.77.6385