Letter to the Editor
Diabetes mellitus associated to treatment with inmunitary checkpoint inhibitors
Diabetes mellitus asociada a tratamiento con inhibidores de los puntos de control inmunitario
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These drugs were initially approved for the treatment of metastatic melanoma, although they are currently used in an increasing number of neoplasms. In this paper, we report the cases of 2 patients who developed diabetes following treatment with 2 of these new molecules: pembrolizumab and durvalumab.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first patient is a 55-year-old male, with no significant personal history, with a brother and son with type 1 diabetes as a family history. Following a diagnosis of advanced melanoma, treatment with pembrolizumab (anti-PD1) monotherapy was initiated. A follow-up blood test at 6 weeks showed a blood glucose level of 353 mg/dl (73−100 mg/dl), without cardinal symptoms. Ketonemia was 1.2 mmol/l, and the pH of 7.38 (7.32–7.42). HbA1c was 7.3% and the patient had a C-peptide of 0.31 ng/ml (0.9–7.1 ng/ml). Pancreatic autoimmunity was positive for anti-GAD and anti-IA2. With these data, the patient was diagnosed with onset of diabetes without cardinal symptoms.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In addition, the patient had developed thyroiditis with drug-induced overt hyperthyroidism. As he was asymptomatic, also in this respect, observation was chosen, and the condition developed into permanent hypothyroidism within a few weeks.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The second patient, a 65-year-old female with no significant personal or family medical history who was diagnosed in 2019 with a stage IIIC epithelial tubo-ovarian carcinoma. Treatment with durvalumab in combination with chemotherapy and bevacizumab, followed by maintenance with durvalumab, bevacizumab and olaparib, was administered as part of a clinical trial. The first course was administered in June 2019. After receiving the 22nd course of treatment in April 2021, the patient came to the emergency department with a 3-day history of asthenia, polyuria and polydipsia. The laboratory data were as follows: blood glucose 750 mg/dl (73−100 mg/dl), ketonemia of 6.2 mmol/l, pH 6.9 (7.32–7.42) and HbA1c 7.5%. The patient’s C-peptide was 0.21 ng/ml (0.9–7.1 ng/ml) and, in this case, pancreatic autoimmunity tests were negative. The study of thyroid and pituitary function did not show relevant changes. The patient was discharged with the diagnosis of onset of diabetes as severe ketoacidosis associated with immunotherapy.</p><p id="par0025" class="elsevierStylePara elsevierViewall">CTLA-4 and PD-1 are molecules on which self-immune tolerance depends. PD-1 is a marker expressed by T-lymphocytes located in peripheral tissues, which transmits inhibitory signals to the immune system by binding to PD-L1 and PD-L2. Although the exact pathophysiological mechanism of this type of diabetes is unknown, it is thought that, following exposure of the beta cell to a stressor, PD-L1 expression on its surface increases, as does the recruitment of CD8 T cells and antigen-presenting cells in the pancreas. When inhibitory treatments of these molecules are administered, this cohort of previously dormant immune cells is likely to be reinforced.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">These 2 cases exemplify the variable clinical expression of this disease. In the first, the significant familial clustering of cases of autoimmune diabetes and the early onset of symptoms, 6 weeks, with a median of 25 weeks, stand out. In the second, the patient had been on treatment for almost 2 years at the time of diabetes onset. Moreover, its clinical onset was in the form of severe ketoacidosis whereas in the first patient it was detected in a routine test.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In both cases, a low HbA1c value was observed, which demonstrates the suddenness with which this disease develops. In up to 67.5% of cases the onset is in the form of ketoacidosis, which is why the name "fulminant diabetes" is beginning to be coined in the literature. The patient usually does not recover from this condition of insulin deficiency, which implies the need for chronic insulin therapy. By contrast, pancreatic autoimmunity is undetectable in 40–50% of patients. In terms of epidemiology, the incidence of this type of diabetes in patients treated with pembrolizumab is estimated at 0.9%, and below 0.1% for durvalumab.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">These observations highlight the importance of close clinical and laboratory monitoring of patients receiving this type of therapy to avoid severe and life-threatening metabolic decompensation, as well as the difficulty in predicting the onset of clinical manifestations.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Z. 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