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Scientific letter
Diabetes mellitus associated with immune checkpoint inhibitors treatment: A clinical case by atezolizumab
Diabetes mellitus asociada al tratamiento con inhibidores de puntos de control inmune: un caso clínico con atezolizumab
Pablo Rodríguez de Vera Gómez
Corresponding author
pablordevera@gmail.com

Corresponding author.
, María del Castillo Tous Romero, Cristóbal Morales Portillo, Isabel Serrano Olmedo, María Asunción Martínez Brocca
Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen Macarena, Sevilla, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In recent times&#44; immunotherapy has taken on an expanding role in cancer treatment&#44; thanks to its positive results compared to classic chemotherapy regimens&#46; However&#44; secondary immune-related adverse events &#40;irAEs&#41; can develop as a result of the alteration of immune tolerance in healthy peripheral tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> We report a case of diabetes mellitus &#40;DM&#41; associated with atezolizumab &#40;a PD-L1 inhibitor&#41;&#44; a rare occurrence in routine clinical practice&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">This was an 82-year-old man diagnosed with stage IV lung adenocarcinoma &#40;bilateral neoplastic lesions and prevascular mediastinal lymphadenopathy&#44; T4N2M1a&#41; treated with atezolizumab monotherapy &#40;1200&#160;mg every 21 days&#41;&#46; In his physical examination and pre-treatment hormonal screening&#44; he was recorded to have a weight of 78&#160;kg&#44; a BMI of 26&#46;8&#160;kg&#47;m<span class="elsevierStyleSup">2</span> and an ECOG performance status of 0&#44; with no abnormalities in his thyroid profile or blood glucose control&#46; He was not found to have any other significant personal or family history with regard to DM&#44; dyslipidaemia&#44; hypertension or anything else&#46; He was not on treatment with corticosteroids or any other additional drugs&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Twenty-four weeks from the start&#44; the patient visited the hospital emergency department with a three-day history of asthenia&#44; polyuria and polydipsia&#44; along with severe asthenia and confusion&#46; Tests showed blood glucose 1078&#160;mg&#47;dl&#44; arterial pH 7&#46;22 with anion gap 16&#160;mEq&#47;l&#44; lactic acid 2&#46;3&#160;mmol&#47;l and urine positive for ketone bodies &#40;equivalent to 30&#8211;40&#160;mg&#47;dl&#41;&#46; The patient&#8217;s creatinine and urea had increased to 1&#46;98&#160;mg&#47;dl and 96&#160;mg&#47;dl&#44; respectively &#40;previously 0&#46;96&#160;mg&#47;dl and 24&#160;mg&#47;dl&#41;&#46; No abnormalities suggestive of exocrine pancreatic involvement were detected&#46; The clinical impression was of new-onset diabetes with severe diabetic ketoacidosis along with secondary acute kidney injury&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The patient&#39;s condition was stabilised within 48&#160;h and he was referred to the Diabetes Day Hospital &#40;DDH&#41;&#44; where he received basic diabetes education and was started on subcutaneous insulin therapy in a basal-bolus regimen &#40;42&#160;U&#47;24&#160;h&#44; 0&#46;54&#160;U&#47;kg&#47;24&#160;h&#41;&#46; Over the following 15 weeks&#44; the patient had five check-up appointments at the DDH coordinated with the Oncology department&#46; He was subsequently referred to the Diabetes Outpatient Clinic for follow-up&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">With a suspected diagnosis of atezolizumab-induced DM&#44; the investigation was broadened to include measurement of C-peptide &#40;0&#46;02&#160;ng&#47;l&#41;&#44; HbA1c &#40;8&#46;6&#37;&#44; 70&#160;mmol&#47;mol&#41;&#44; anti&#8211;&#946;-cell antibodies &#40;with a negative result&#41; and genetic determination of risk HLA class II &#40;with a positive result for DQ2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The results and changes over time in laboratory values are shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The patient&#8217;s insulin requirements did not subsequently significantly decrease over the course of follow-up&#46; Currently&#44; his suboptimal metabolic control persists &#40;HbA1c &#62;8&#46;5&#37;&#41;&#46; In oncology follow-up&#44; no tumour progression was found and he had no thyroid or cardiovascular problems &#40;diabetes of recent onset&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Atezolizumab is an anti PD-L1 monoclonal antibody of the immune checkpoint inhibitor &#40;ICI&#41; family approved for the treatment of breast&#44; urothelial and non-small cell lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Its mechanism of action is aimed at blocking membrane proteins &#40;PD-1&#44; PD-L1 or CTLA-4&#41; that trigger inhibitory signals in T lymphocytes&#44; with the goal of increasing their ability to act against cancer cells&#46; Because immune control mechanisms are altered&#44; endocrine irAEs &#40;especially thyroid&#41; are common&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However&#44; the development of ICI-induced DM &#40;ICI-DM&#41; is very rare &#40;estimated incidence 0&#46;2&#37;&#8211;1&#46;4&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The only report in Spain we were able to find was a 2019 case report by Le&#243;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> in relation to durvalumab&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The time of onset from the start of treatment is variable&#44; with a median of around 15&#8211;20 weeks&#46; ICI-DM has specific characteristics that distinguish it from other forms of autoimmune DM&#46; It develops suddenly&#44; often with ketoacidosis &#40;71&#37;&#41; and C-peptide levels close to 0 &#40;persistent insulin deficiency&#41;&#44; which makes it difficult to predict&#46; In our case&#44; in week 21 a blood glucose level of 112&#160;mg&#47;dl was detected in a routine test and was not considered clinically significant &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This would suggest that&#44; should slight abnormalities in blood glucose levels be detected&#44; it could be beneficial to start the diagnostic process early&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In ICI-DM&#44; there are no transitory remission periods &#40;&#8220;honeymoon periods&#8221;&#41;&#44; and insulin requirements remain constant over time&#46; By contrast&#44; in type 1 DM and latent autoimmune diabetes in adults &#40;LADA&#41;&#44; periods of up to two years with normal C-peptide levels are common&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> HbA1c levels may be normal at diagnosis due to the rapid development of the disease &#40;in our case&#44; the determination was made 8 weeks after onset&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> These characteristics are similar to fulminant DM in Asian populations&#44; so they could share pathophysiological mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">While in type 1 DM over 90&#37; of cases are positive for at least one anti-&#946;-cell antibody&#44; in ICI-DM this has only been found in 50&#37;&#44; with anti-GAD65 being the most common&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In addition&#44; Stamatouli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> suggested an association between the presence of the HLA class II-DR4 allele and the development of ICI-DM&#46; Other risk haplotypes for type 1 DM that might predispose an individual to ICI-DM are DR4&#47;DQ8 and DR3&#47;DQ2&#44; although a larger number of cases must be studied to confirm that relationship&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">For the follow-up of patients starting treatment with ICI&#44; periodic blood glucose determinations could be useful&#44; along with detailed information for the patient about suggestive symptoms&#44; and mechanisms in place for early consultation should any of those symptoms appear&#46; There is no consensus on systematic HbA1c and anti-&#946; cell antibody screening because of their apparent low predictive value&#44; despite the fact that they are the tests of choice in classic forms of DM and can add value once the event has occurred&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8</span></a> The determination of pancreatic markers of exocrine damage &#40;such as pancreatic lipase&#41;&#44; elevation of which has been demonstrated in up to 90&#37; of cases of fulminant DM in Asian populations&#44; could also be considered&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Despite the low incidence of ICI-DM&#44; the number of cases will most likely increase over the coming years with the gradual expansion of the use of these drugs in routine clinical practice&#46; Consequently&#44; we find it essential not only to know about ICI-DM&#44; but also to report it so that multidisciplinary management strategies involving Oncology and Endocrinology may be planned&#46; For this purpose&#44; we propose the DDH model as an optimal resource&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Authorship</span><p id="par0065" class="elsevierStylePara elsevierViewall">All the authors declare that they contributed substantially to the concept of the study&#44; drafting of the manuscript and approval of the submitted version of this article&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; de Vera G&#243;mez PR&#44; Tous Romero MC&#44; Portillo CM&#44; Olmedo IS&#44; Brocca MAM&#46; Diabetes mellitus asociada al tratamiento con inhibidores de puntos de control inmune&#58; un caso cl&#237;nico con atezolizumab&#46; Endocrinol Diabetes Nutr&#46; 2021&#59;68&#58;363&#8211;365&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Timeline and changes over time in laboratory values&#46; Results are included according to the atezolizumab cycle number and treatment week&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span><span class="elsevierStyleItalic">HLA class II&#46;</span> DQ allele&#58; DQ2 &#40;DQA1&#42;05&#58;01-DQB1&#42;02&#58;01&#41; DQ7 &#40;DQA1&#42;0201-DQB1&#42;0301&#41;&#46; DR allele not available&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span><span class="elsevierStyleItalic">Anti&#8211;&#946;-cell antibody&#46;</span> Anti-pancreatic islet cell antibodies &#40;ICAs&#41; dilution &#60;1&#47;5 &#40;negative&#41;&#44; anti-glutamic acid decarboxylase 65 &#40;GAD65&#41;&#58; 5&#46;82&#160;U&#47;mL &#40;0&#46;0&#8211;17&#46;0&#41;&#44; anti-insulin antibodies &#40;AIAs&#41;&#58; 7&#46;9&#160;U&#47;mL &#40;0&#46;0&#8211;20&#46;0&#41;&#44; anti-tyrosine phosphatase antibodies similar to insulinoma-associated antigen 2 &#40;IA2&#41;&#58; 6&#46;87&#160;U&#47;mL &#40;0&#46;0&#8211;27&#46;0&#41;&#46; Anti-zinc transporter 8 &#40;ZnT8&#41;&#58; Not available&#46;</p>"
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                      "titulo" => "Immune checkpoint inhibitor diabetes mellitus&#58; a novel form of autoimmune diabetes"
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                        0 => array:2 [
                          "etal" => true
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Article information
ISSN: 25300180
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos