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      Combination immune checkpoint inhibitor therapy nivolumab and ipilimumab associated with multiple endocrinopathies

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      Endocrinology, Diabetes & Metabolism Case Reports
      Bioscientifica Ltd

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          Immune checkpoint inhibitors are the mainstay of treatment for advanced melanoma, and their use is being increasingly implicated in the development of autoimmune endocrinopathies. We present a case of a 52-year-old man with metastatic melanoma on combination nivolumab and ipilumimab therapy who developed concurrent hypophysitis, type 1 diabetes mellitus (T1DM) and diabetes insipidus. He presented prior to third cycle of combination treatment with a headache, myalgias and fatigue. Biochemistry and MRI pituitary confirmed anterior pituitary dysfunction with a TSH: 0.02 mU/L (0.5–5.5 mU/L), fT4: 5.2 pmol/L (11–22 pmol/L), fT3: 4.0 pmol/L (3.2–6.4 pmol/L), cortisol (12:00 h): <9 nmol/L (74–286 nmol/L), FSH: 0.7 IU/L (1.5–9.7 IU/L), LH: <0.1 IU/L (1.8–9.2 IU/L), PRL: 1 mIU/L (90–400 mIU/L), SHBG: 34 nmol/L (19–764 nmol/L) and total testosterone: <0.4 nmol/L (9.9–27.8 nmol/L). High-dose dexamethasone (8 mg) was administered followed by hydrocortisone, thyroxine and topical testosterone replacement. Two weeks post administration of the third cycle, he became unwell with lethargy, weight loss and nocturia. Central diabetes insipidus was diagnosed on the basis of symptoms and sodium of 149 mmol/L (135–145 mmol/L). Desmopressin nasal spray was instituted with symptom resolution and normalization of serum sodium. Three weeks later, he presented again polyuric and polydipsic. His capillary glucose was 20.8 mmol/L (ketones of 2.4 mmol), low C-peptide 0.05 nmol/L (0.4–1.5 nmol/L) and HbA1c of 7.7%. T1DM was suspected, and he was commenced on an insulin infusion with rapid symptom resolution. Insulin antibodies glutamic acid decarboxylase (GAD), insulin antibody-2 (IA-2) and zinc transporter-8 (ZnT8) were negative. A follow-up MRI pituitary revealed findings consistent with recovering autoimmune hypophysitis. Immunotherapy was discontinued based on the extent of these autoimmune endocrinopathies.

          Learning points:
          • The most effective regime for treatment of metastatic melanoma is combination immunotherapy with nivolumab and ipilumimab, and this therapy is associated with a high incidence of autoimmune endocrinopathies.

          • Given the high prevalence of immune-related adverse events, the threshold for functional testing should be low.

          • Traditional antibody testing may not be reliable to identify early-onset endocrinopathy.

          • Routine screening pathways have yet to be adequately validated through clinical trials.

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          Precipitation of Autoimmune Diabetes With Anti-PD-1 Immunotherapy

          Immunotherapy targeting T-cell regulatory molecules is highly effective in multiple cancers refractory to standard chemotherapies. However, blocking inhibitory molecules on activated T cells not only increases tumor cell destruction but also can breach tolerance, enabling pathological T cells to react with self-antigens. Indeed, autoimmune endocrinopathies, including hypophysitis, hypopituitarism, and thyroiditis, have been reported in trials involving anti-CTLA-4 and anti-PD-1 monoclonal antibodies (1–3). But autoimmune diabetes has not been definitively linked to these agents. We describe the development of new-onset insulin-dependent diabetes in five patients after receiving anti-PD-1 antibodies, either as single agent or in combination with other cancer drugs. Clinical history and key laboratory findings are summarized in Table 1. Notably, while the patients presented with diverse cancer types, and some had been treated with other immunological agents, their histories were common for anti-PD-1 antibody exposure prior to developing autoimmune diabetes. Time from drug administration to diabetes onset spanned 1 week to 5 months, when patients presented with severe hyperglycemia or diabetic ketoacidosis (DKA) with elevated HbA1c. Diabetes was a new diagnosis for all but one patient who had preexisting type 2 diabetes controlled with metformin. Most patients exhibited inappropriately low or undetectable C-peptide (Table 1). All were initiated on insulin therapy upon presentation and remained insulin-dependent for glucose control. Table 1 Clinical history and key laboratory findings Patient Age/sex Primary diagnosis Pertinent history Anti-PD-1 drug Other chemotoxins Diabetes presentation Random C-peptide* and glucose Time after anti-PD-1 Antibody positivity/titers^ HLA Diabetes antigen-specific T cells† 1 55/F Melanoma Autoimmune thyroid disease Nivolumab Ipilimumab, prednisone DKA, glucose 532 mg/dL, HbA1c 6.9% (52 mmol/mol) 55 years). Not only do our cases demonstrate temporal correlation between anti-PD-1 treatment and diabetes onset, they also provide the first mechanistic support for cancer immunotherapies targeting T-cell regulatory pathways to precipitate autoimmune diabetes. Other factors that may influence predisposition for hyperglycemia and autoimmunity in our patients included combined use with other immune modulators (patient 1), pancreatic metastases (patient 3), and preexisting type 2 diabetes (patient 4). Nonetheless, the fact that they all developed acute severe hyperglycemia with ketoacidosis or low/undetectable C-peptide levels is strong evidence for a new and insulin-deficient type of diabetes. Diabetes had previously been reported as an adverse event to anti-PD-L1 (2) and one case was reported in 206 subjects treated with nivolumab (3), but there lacked evidence for an autoimmune mechanism. Our report demonstrates humoral and cellular autoimmunity in multiple patients with anti-PD-1–induced diabetes. While it is difficult to estimate the true incidence of this phenomenon, the five patients in our series represent less than 3% of total subjects who have participated in PD-1/PD-L1 trials at our institution. These cases illustrate the importance of recognizing this potential precipitant of autoimmune diabetes in older individuals receiving immunotherapy.
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            Fulminant type 1 diabetes mellitus with anti‐programmed cell death‐1 therapy

            Abstract Anti‐programmed cell death‐1 (PD‐1) antibodies are regarded as a risk factor for insulin‐dependent diabetes mellitus as a side‐effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin‐dependent diabetes during anti‐PD‐1 therapy. A 55‐year‐old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C‐peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti‐PD‐1 therapy can cause rapid onset of insulin‐dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti‐PD‐1 therapy.

              Author and article information

              Endocrinol Diabetes Metab Case Rep
              Endocrinol Diabetes Metab Case Rep
              Endocrinology, Diabetes & Metabolism Case Reports
              Bioscientifica Ltd (Bristol )
              28 February 2018
              : 2018
              : 17-0146
              [1]Geelong University Hospital , Barwon Health, Geelong, Victoria, Australia
              Author notes
              Correspondence should be addressed to F Gunawan Email: Florence.a.gunawan@ 123456gmail.com
              © 2018 The authors

              This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

              : 20 December 2017
              : 16 January 2018
              Unusual Effects of Medical Treatment


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