Immune-mediated diabetes associated with pembrolizumab

Bodoque Cubas, Javier; Salazar González, Juan José; Miret Llauradó, Marcel.la

doi:10.1016/j.medcle.2023.02.010

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"etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Juan José" "apellidos" => "Salazar González" ] 2 => array:2 [ "nombre" => "Marcel.la" "apellidos" => "Miret Llauradó" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Hospital de Tortosa Verge de la Cinta, Tortosa, Tarragona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diabetes inmunomediada asociada a pembrolizumab" ] ] "textoCompleto" => "This article has been submitted in accordance with the indications of our centre's health care ethics committee after obtaining the patient's informed consent.Immunotherapy has changed the course of the disease for many cancer patients.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> However, as it blocks immune checkpoints, it can be associated with autoimmune reactions, including immune-mediated diabetes.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>We report the case of a 66-year-old male, with a history of grade I obesity, diagnosed with stage IV lung squamous cell carcinoma treated with several courses of pembrolizumab, who was referred to the emergency department for severe diabetic ketoacidosis (DKA) after the 12th course of pembrolizumab.Physical examination revealed sinus tachycardia and Kussmaul's breathing. The patient remained afebrile, maintaining a BP of 135/87mmHg with a heart rate of 110 bpm. He reported cardinal symptoms of diabetes with polydipsia and polyuria in previous months, but not weight loss.The venous blood gases on arrival at the ED showed a pH of 6.82 (NV: 7.35–7.45) with a blood glucose of 376mg/dl, natraemia of 125 mEq/l (NV: 135–145 mEq/l), kalaemia of 4.1 mEq/l (NV: 3.5–5 mEq/L) and lactic acid of 4.01mmol/l (NV: 0.36–1.33mmol/l). The capillary ketonemia determination was 4.4mmol/l (NV: <1mmol/l). The blood test showed a blood glucose of 312mg/dl, a glycosylated haemoglobin (Hb1Ac) of 9.4% (NV <5.4%), creatinine of 0.79mg/dl (NV: 0.7–1.3mg/dl), natraemia of 136 mEq/l (NV: 135–145 mEq/l) and kalaemia of 3.4 mEq/l (NV: 3.5–5 mEq/l). After evaluation by Endocrinology, treatment was started with IV hydration therapy and intravenous insulin perfusion, with improvement of metabolic parameters and reversal of DKA.Treatment was started on an outpatient basis with a basal bolus regimen and a new follow-up was requested one month after the onset of the symptoms. The control CBC showed a Hb1Ac of 8.7% with C-peptide levels <0.05ng/ml (NV: 0.81–3.85ng/ml), with anti-glutamate decarboxylase (GAD) antibodies <5 U/ml (positive if >5 U/ml) and pancreatic anti-slots (IA2) <7.5 U/ml (positive if >7.5U/ml).A review of previous blood tests showed elevated fasting blood glucose levels since the eighth course of pembrolizumab. Subsequently, no blood glucose tests were performed until the tenth and eleventh courses of the drug were administered, when he already met the diagnostic criteria for diabetes, as he had fasting blood glucose levels of 146mg/dl and 162mg/dl, respectively.Literature cases of immune-mediated diabetes mellitus secondary to the use of PDL-1 inhibitors (pembrolizumab and ipilimumab) have been reported.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Although the frequency of presentation is low (0.1-0.2%), most patients start as DKA.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> However, in most of the cases described, fasting blood glucose or Hb1Ac levels were altered in the months prior to onset, demonstrating that pancreatic beta cell destruction possibly occurs progressively.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>The responsible mechanism is a destruction of pancreatic cells by the T cells, which are no longer inhibited by PDL1.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The destruction of beta cells results in the release of intracellular proteins, such as glutamic acid decarboxylase or GAD, and a percentage of these patients may be found to have positive anti-GAD antibodies at diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> However, in approximately 50% of the cases reported, pancreatic immunology is negative, and we must rely primarily on C-peptide levels to confirm the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>It should be noted that, due to its low incidence, it has not been clearly established which patients are most susceptible to developing immune-mediated diabetes, so serial fasting blood glucose, glycosylated haemoglobin and C-peptide monitoring is recommended prior to the administration of each course of treatment.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> At the same time, the warning signs of diabetic onset should be explained.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> On the other hand, it is recommended that patients with a history of autoimmune diseases should be provided with a glucometer for self-testing of capillary blood glucose in case of having compatible symptoms.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a>Based on these findings, we consider it important to keep in mind the possibility of developing immune-mediated diabetes in patients treated with PDL-1 inhibitors because most of the described cases start as DKA that could have been avoided if the referral endocrinology unit had been consulted and treatment had been optimised based on simple fasting serum/capillary blood glucose, Hb1Ac and C-peptide tests.FundingNo private or public funding source has been obtained.Conflict of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "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" => "A paradigm shift in cancer immunotherapy: From enhancement to normalization" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.F. Sanmamed" 1 => "L. Chen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cell.2018.09.035" "Revista" => array:6 [ "tituloSerie" => "Cell" "fecha" => "2018" "volumen" => "175" "paginaInicial" => "313" "paginaFinal" => "326" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30290139" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: A systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Barroso-Sousa" 1 => "W.T. Barry" 2 => "A.C. Garrido-Castro" 3 => "F.S. Hodi" 4 => "L. Min" 5 => "I.E. Krop" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2017.3064" "Revista" => array:6 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2018" "volumen" => "4" "paginaInicial" => "173" "paginaFinal" => "182" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28973656" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Clotman" 1 => "K. Janssens" 2 => "P. Specenier" 3 => "I. Weets" 4 => "C.E. De Block" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2018-00728" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2018" "volumen" => "103" "paginaInicial" => "3144" "paginaFinal" => "3154" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29955867" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Precipitation of autoimmune diabetes with anti-pd-1 immunotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Hughes" 1 => "N. Vudattu" 2 => "M. Sznol" 3 => "S. Gettinger" 4 => "H. Kluger" 5 => "B. Lupsa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc14-2349" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2015" "volumen" => "38" "paginaInicial" => "e55" "paginaFinal" => "e57" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25805871" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune diabetes associated with pembrolizumabs: a review of published case reports" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Cheema" 1 => "B. Makadia" 2 => "T. Kawardia" 3 => "R. Bajwa" 4 => "M. Hossain" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.14740/wjon1085w" "Revista" => array:6 [ "tituloSerie" => "World J Oncol" "fecha" => "2018" "volumen" => "9" "paginaInicial" => "1" "paginaFinal" => "4" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29581809" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000016100000001/v2_202311101438/S2387020623002371/v2_202311101438/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000016100000001/v2_202311101438/S2387020623002371/v2_202311101438/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623002371?idApp=UINPBA00004N"]

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Vol. 161. Issue 1.

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