New-onset insulin-dependent diabetes due to nivolumab

in Endocrinology, Diabetes & Metabolism Case Reports

Summary

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab.

Learning points:

  • Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1).

  • Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1.

  • Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents.

Summary

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab.

Learning points:

  • Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1).

  • Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1.

  • Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents.

Background

Understanding how cancer escapes host immune regulation has led to the development of cancer ‘immunotherapy’. In particular, antibodies such as nivolumab, targeting and inhibiting programmed cell death 1 receptor (PD-1(PDCD1)), can result in the preferential activation of T-cells with specificity for cancer (1). Multiple trials have already demonstrated significant response rates and improved survival with nivolumab in multiple neoplasms including melanoma (2, 3, 4, 5, 6, 7, 8, 9, 10, 11), non-small-cell lung cancer (NSCLC) (2, 3, 4, 12, 13, 14, 15) and renal cell carcinoma (RCC) (2, 3, 4, 16, 17).

However, inhibition of the PD-1 pathway results in a reduction of ‘self-tolerance’, with an apparent increase in immune-mediated adverse events (AE). Clinical trials investigating the efficacy of nivolumab in cancers have reported increased rates of autoimmune endocrinopathies, including: hypophysitis (5, 7, 8, 10, 11), adrenal insufficiency (4, 5, 7, 10, 12), thyroid disorders (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18) and hyperglycemia (2, 3, 4, 6, 8, 15, 17). We report a patient presenting critically ill with diabetic ketoacidosis (DKA) after receiving nivolumab. In addition, we provide a review of the literature reporting nivolumab-induced diabetes mellitus (DM). Acute care physicians’ awareness of the acute complications of these novel therapies is essential for the timely management of these critically ill patients.

Case presentation

A Caucasian man, in his early seventies, reported to our emergency department with 3 days of dyspnea, abdominal pain, fatigue and polyuria. Symptoms were progressive despite drinking a significant amount of fluids to keep up with his subjective sense of dehydration. He denied fever, chest pain, edema and visual disturbances.

One year earlier, he had undergone radical right nephrectomy and retroperitoneal lymph node dissection for stage IVB metastatic RCC (metastases to mesenteric lymph nodes and peritoneum). He had received 3 cycles of nivolumab, 3 mg/kg (300 mg, weight: 90 kg with BMI of 28.4) intravenously every 2 weeks, with his last infusion 10 days prior to his acute presentation. Notably, the patient was not enrolled in a clinical trial.

Other comorbidities were hypertension and chronic kidney disease that did not require renal replacement therapy. He was on lisinopril and aspirin. He had not been on any systemic glucocorticoids. There was no personal or family history of pancreatitis, DM or other autoimmune disorders.

Patient was afebrile and normotensive with a pulse of 88 beats per minute, respiratory rate of 28 breaths per minute and oxygen saturation of 97% while breathing ambient air. On examination, he was in moderate respiratory distress due to hyperpnea. There was absent breath sounds on the left lung base with dullness to percussion and decreased tactile vocal fremitus. The rest of his examination was unremarkable. Chest radiographs showed small bilateral pleural effusions (left greater than right) but otherwise clear lung fields.

Investigation

Laboratory analyses (Table 1) showed severe hyperglycemia (878 mg/dL) and an anion gap metabolic acidosis (anion gap: 21) associated with ‘large’ serum acetones and urine ketones. Arterial blood gas confirmed a primary metabolic acidosis (pH: 7.23, HCO3: 12) with partial respiratory compensation (PaCO2: 18). Multiple pre-admission outpatient fasting blood glucose levels, as recently as two weeks prior to admission, were normal (86–100 mg/dL), although the HbA1c at admission was increased at 8.4%. Other metabolic derangements (hyponatremia and hyperkalemia) were related to ketoacidosis. Additional workup for possible acute pancreatitis, acute coronary syndrome or infectious process was unrevealing. A random C-peptide level was low (0.4 ng/mL) with concomitant blood glucose of 194 mg/dL. Serum for glutamic acid decarboxylase (GAD65) antibody was drawn at the time of the acute presentation, and when it proved negative on follow-up, testing for other less common autoantibodies (IA-2 and IAA) and human leukocyte antigen typing was considered but deferred by the patient and clinical team given unclear management implications (19).

Table 1

Laboratory data.

VariableReference range, adultResult
Erythrocyte count (×1012/L)4.32–5.723.3
Hematocrit (%)38.8–50.029.5
Hemoglobin (g/dL)13.5–17.59.0
Mean corpuscular volume (fL)81.2–95.189.4
White cell count (×109/L)3.5–10.520.4
Differential count (%)
 Neutrophils44.4–70.995.1
 Lymphocytes17.8–41.50.8
 Monocytes4.7–14.83.7
 Eosinophils1.0–7.00
Platelet count (×109/L)150–450522
Sodium (mmol/L)135–145125
Potassium (mmol/L)3.6–5.26.6
Chloride (mmol/L)98–10792
Bicarbonate (mmol/L)22–2912
Glucose (mg/dL)70–100878
Blood urea nitrogen (mg/dL)8–2441
Creatinine (mg/dL)0.8–1.232.6
Total protein (g/dL)6.3–7.96.7
Albumin (g/dL)3.5–5.03.3
Bilirubin, total (mg/dL)≤1.20.3
Magnesium (mg/dL)1.8–2.52.7
Calcium8.9–10.18.7
Alkaline phosphatase (U/L)45–115108
Alanine aminotransferase (U/L)7–5514
Aspartate aminotransferase (U/L)8–4884
Lipase (U/L)7–60118
Amylase (U/L)26–10227
Prothrombin time (s)11.6–14.713.1
International normalized ration0.8–1.11.0
Activated partial thromboplastin time (s)22.7–36.135.4
B-type natriuretic peptide≤67206
Troponin T (ng/mL)0.00–0.10<0.01
Thyroid-stimulating hormone (IU/L)0.3–4.21.5
Hemoglobin A1C (%)<6.58.4
C-peptide (ng/mL)1.1–4.40.4
Arterial blood gas
 pH7.35–7.457.23
 PaCO2 (mmHg)35–4517.6
 PaO2 (mmHg)80–10099
Urine analysis
 Specific gravity1.002–1.0301.016
 Leukocyte esteraseNegativeNegative
 NitriteNegativeNegative
 pH5.0–8.05.0
 Protein (mg/dL)Negative10
 Glucose (g/dL)Negative>1
 BilirubinNegativeNegative
 UrobilinogenNormal
 Erythrocyte (cell/hpf)0–2<1
 White cell (cell/hpf)
Acetone bloodNegativeLarge
Lactate (mmol/L)0.9–1.71.4
Ammonia (µmol/L)0–3018
Glutamic acid decarboxylase (GAD65) antibody (nmol/L)≤0.020.00

Estimated glomerular filtration rate (eGFR) was 25 mL/min/1.73 m2; baseline Cr is 1.8–2.2 mg/dL.

Treatment

The patient was diagnosed with DKA due to new-onset insulin-dependent autoimmune diabetes secondary to nivolumab. He was treated accordingly with intravenous hydration, insulin drip and electrolyte replacement. Thereafter, all the metabolic disturbances improved with resolution of hyperglycemia and acidemia. However, he continued to require insulin therapy and was subsequently discharged on subcutaneous insulin.

Outcome and follow-up

On follow-up, restaging computed tomography showed significant disease progression without pancreatic involvement. Nivolumab was stopped and changed to pazopanib (tyrosine kinase inhibitor). Despite remaining off PD-1 antagonists, the patient continued to require multiple daily insulin injections with insulin glargine (15 units twice daily) and aspartate (5 units with meals, weight 76 kg) at his last follow-up 7 months after hospital discharge. The patient subsequently died 8 months after his initial presentation due to complications of his metastatic RCC.

Discussion

Even though GAD65 antibodies were negative, the inappropriately low C-peptide and sudden onset and persistent hyperglycemia with presentation of DKA confirmed insulin-dependent DM. The repeatedly normal pre-nivolumab fasting blood glucose levels suggest the absence of diabetes prior to nivolumab, while the increased HbA1c at the time of admission suggests more proximal post-nivolumab development of hyperglycemia, diabetes and glycation of hemoglobin. In all, this affirms the causal relationship between nivolumab and the new-onset DM presenting as DKA in our patient.

We performed an extensive literature search of Medline database through February 2018 to identify all published case reports of anti-PD-1-induced DM. Search term used was nivolumab, pembrolizumab and ipilimumab. For each report, we extracted age, gender, cancer type, nature and time frame of presentation, HbA1c, presence of autoantibodies, prior or concurrent chemotherapeutics, systemic steroids use and whether anti-PD-1 therapy was resumed. Reports’ references were screened and all pertinent case reports were added. Additionally, we had previously performed a comprehensive literature search to identify all published articles that have investigated the impact of nivolumab on patients with cancer. Search term used was nivolumab and limits applied were: human and English. We reviewed the title and abstract of each article for possible inclusion. Articles that explored the effect of nivolumab on patients with cancer were included. For each included study, the information extracted included cancer type, study period, study design, sample size, gender, nivolumab dose, AE including common terminology criteria for adverse events (CTCAE) grade 3 or 4, and specifically, rates of endocrinopathy. Published manuscripts and supplemental materials were reviewed thoroughly for rates of treatment-related AE. Data about AE of any grade and of grade 3 or higher were gathered. Rates of thyroid disease, hypothyroidism and/or hyperthyroidism, were registered. Rates of hyperglycemia and rates of DM diagnosis, if reported, were also assembled and presented in tabular format. Our literature search produced 155 potential literature citations. After reviewing studies’ title and/or abstract, a total of 17 studies were included (details are outlined in Tables 2 and 3).

Table 2

Characteristics of observational studies.

StudyPhaseCancerStudy periodSample sizeMale n (%)Nivolumab dose (mg/kg every 2 weeks)Safety outcome CTACE* n (%)Endocrinopathyn (%)
Any gradeGrade 3–4ThyroidHyperglycemia
(2)1Melanoma, CRC, prostate, NSCLC, RCC1/20103922 (56)0.3, 1, 3, 1059 AE in 39 patients15 AE grade 3 in 39 patients1 (2.6)1 (3)
(3)§1Melanoma, CRC, prostate, NSCLC, RCC2/2012296195 (66)0.1, 0.3, 1, 3, 10207 (70)41 (14)10 (3)2 (1)
(4)§1Melanoma, CRC, prostate, NSCLC, RCC2/2012207121 (58)0.1, 0.3, 1, 3, 10126 (61)19 (9)6 (3)3 (1)
(5)1Melanoma2/20138650 (58)0.3, 1, 3, 1073 (85)34 (40)6 (7)NR
(6)1Melanoma2008–201210772 (67)1, 3, 1090 (84)24 (22)8 (7)2 diabetes event rate per 100 person-years of exposure (12–24 months)
(18)1Hodgkin’s lymphoma6/20142312 (52)318 (78)5 (22)2 (9)NR
(7)1MelanomaNR3318 (55)1, 3, 10286 (60)5 in 4 patients7 (21)NR
(12)2NSCLC (squamous)11/2012–7/201311785 (73)387 (74)20 (17)6 (5)NR
(16)1RCC2008–20123426 (76)1, 1029 (85)6 (18)3 (9)NR
(13)1NSCLC11/2008–1/201212979 (61)1, 3, 1091 (71)18 (14)

*Number of total patients assessed for adverse events may be different from patients included in the study; patients may had more than one adverse events; related adverse events if it was reported; any grade; related adverse events if it was reported; does not specify if diabetes or not; §same patient population; escalating doses of nivolumab and ipilimumab administered concurrently or sequentially; 8 (6%) endocrinopathy (no further details).

CTCAE, common terminology criteria for adverse events; NR, not reported.

Table 3

Characteristics of randomized controlled trials.

AuthorsPhaseCancerStudy periodDesign (control group)Male n(%)Nivolumab dose (mg/kg every 2 weeks)Safety outcome (CTACE)* n (%)Endocrinopathyn (%)
Any gradeGrade 3–4ThyroidHyperglycemia
(8)3Melanoma1/2013–2/2014Dacarbazine246 (59)3192 (93)70 (34)16 (8)1 (0.5)
(9)3Melanoma12/2012–1/2014Standard chemotherapy261 (64)3181 (68)24 (9)20 (7)NR
(10)1MelanomaNRCombined with ipilimumab vs ipilimumab monotherapy95 (67)1, 386 (91)51 (54)22 (23)NR
(11)3Melanoma7/2013–3/2014Nivolumab monotherapy vs combined with ipilimumab vs ipilimumab monotherapy610 (65)1, 3311 (99)136 (45)40 (13)NR
(14)3NSCLC (squamous)10/2012–12/2013Docetaxel208 (76)376 (58)9 (7)5 (4)NR
(17)3RCC10/2012–3/2013Everolimus619 (75)3319 (79)76 (19)NR9 (2)§
(15)3NSCLC (non-squamous)11/2012–12/2013Docetaxel319 (55)3199 (69)30 (10)23 (8)13

*Number of total patients assessed for adverse events may be different from patients included in the study; patients may had more than one adverse events; related adverse events if it was reported; any grade; related adverse events if it was reported; with diabetes; §does not specify if diabetes or not; no cases of diabetes.

CTCAE, common terminology criteria for adverse events; NR, not reported.

Multiple trials have reported hyperglycemia as a potential AE with estimated risks of 0.5–11% (details are outlined in Tables 2 and 3). However, only three studies have reported on the outcome of formally diagnosed DM. An observational study by Topalian et al. (6) reported a rate of 2 cases of DM per 100 person-years of exposure with all cases being diagnosed after the first year of therapy. A randomized controlled trial (RCT) by Robert et al. (8) reported 1 case of DM in 206 melanoma patients. Another RCT by Borghaei et al. (15) reported 13 cases of hyperglycemia in 287 patients with non-squamous NSCLC but none were diagnosed with DM. None of the studies reported if hyperglycemia cases presented with DKA. There has been a growing number of case reports of patients diagnosed with autoimmune diabetes following anti-PD-1 therapy. A comprehensive characteristic of these cases is summarized in Table 4. We have identified 42 cases of anti-PD-1-induced DM. The mean age is 61 years. There is no apparent gender or cancer preference though most cases were reported in patients with melanoma and NSCLC. Almost two-thirds of cases presented with DKA and within a time frame ranging from 1 week up to 1 year. About half of the cases had negative autoantibody serologies. Only two cases (20, 21) received systemic steroids specifically for pembrolizumab-induced DM. However, neither showed improvement nor resolution of DM. Half of the cases, resumed anti-PD-1 therapy after resolution of DKA or control of hyperglycaemia without further deterioration in DM control. Interestingly, we found two cases (22, 23) of autoimmune DM in patients with melanoma who received ipilimumab monotherapy (a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody).

Table 4

Characteristics of case reports of patients diagnosed with diabetes after receiving anti-PD-1 therapy.

StudyAgeSexCancerPresentationTime FrameHbA1c (%)AutoantibodiesPrior or concurrent chemotherapeuticsManagement
Systemic steroidResumed anti-PD-1
Nivolumab
 (19)55FMelanomaDKA5 months6.9NoneIpilimumabNRNR
83FNSCLCDKA<1 month7.7GAD65NoneNRNR
63MRCCHyperglycemia4 months8.2GAD65, IA-2, IAAAldesleukin, bevacizumab, interferonNRNR
58MSCLCDKA1 week9.7GAD65Carboplatin, etoposide, paclitaxelNRNR
 (29)70MNSCLCHyperglycemia15 weeks9.8NoneNRNRNR
66FSCC JawDKA7 weeks9.4GAD65NRNRNR
 (30)72MHodgkin lymphomaHyperglycemia57 days7.3NoneABVD, brentuximabNRYes
 (31)66FMelanomaDKA4 months7.3NoneNoneNRYes
 (32)70FMelanomaHyperglycemia6 weeksNRNoneNoneNRYes
40MMelanomaNR6 weeksNRNRDacarbazine, polychemotherapy, ipilimumabNRYes
78FMelanomaDKA3 weeksNRGAD65Dacarbazine; ipilimumabNRNR
 (33)55FMelanomaHyperglycemia1 year7NoneIpilimumab, dacarbazine, nimustine, cisplatin, tamoxifenNRYes
 (34)73MMelanomaDKA6 weeks8.8GAD65, ZnT8A, IA-2Interferon, vemurafenib, cobimetinibNRYes
 (35)l63FMelanomaDKA30 weeks8.9NoneDacarbazineNRNo
 (36)54FMelanomaHyperglycemia10 months7NoneCisplatin, dacarbazine, nimustine and tamoxifenNRYes
 (37)34FNSCLCDKA4 weeks7.1GAD65, IA-2, IAACarboplatin, pemetrexedNRNo
 (38)68FRCCHyperglycemia98 days6.9NoneInterferon, sunitinib, axitinibNRYes
 (39)NRNRNSCLCNRNRNRNRNRNRNR
 (40)63MNSCLCDKA27 days7.2GAD65Carboplatin, paclitaxel, cisplatinNRNo
 (41)83MSCC maxillary sinusDKA3 months7.4GAD65NoneYes*No
 (42)31MNSCLCDKA13 days6.4GAD65NRNRYes
62FNSCLCHyperglycemia10 weeks6.5NoneNRNRYes
 (43)54MMelanomaDKA4 monthsNRGAD65IpilimumabYes*No
 (44)55MPleomorphic carcinomaDKA10 days after cycle 98.2NoneCisplatin, docetaxel, pemetrexedNRNo
 (45)42MMelanomaDKA3 months6.5NoneIpilimumabYes*NR
 (46)74FNSCLCDKA25 days8.7GAD65PemetrexedNRNR
 (47)66MMelanomaHyperglycemia19 daysNRGAD65, IA-2IpilimumabYes*No
 (48)73MNSCLCHyperglycemia25 weeks9.4NoneNRNRNo
 (49)40MHodgkin lymphomaNRNRNRGAD65COPP, brentuximab, gemcitabine, ICENRNR
 This case70MRCCDKA6 weeks8.4NoneNoneNoNo
Pembrolizumab
 (19)64FMelanomaHyperglycemia<1 month7.4NoneNoneNRNR
 (50)54FMelanomaDKAAfter cycle 3NRGAD65IpilimumabNRYes
 (51)44FMelanomaDKA2 weeks after cycle 26.85NoneNRNRYes
 (52)55MMelanomaDKACycle 910.7NoneDacarbazine, ipilimumabNRNo
 (53)58MMelanomaHyperglycemia1 year9.7GAD65Interferon, vemurafenib, IL-2, ipilimumabNoNo
 (32)58FMelanomaHyperglycemia3 weeksNRGAD65IpilimumabNRYes
 (21)76MNSCLCHyperglycemia4 weeks5.8GAD65, IA-2Carboplatin, paclitaxelYesYes
 (20)60MMelanomaDKA5 weeks7.1NoneIpilimumabYesNo
 (54)58MMelanomaDKA3 months7.4NoneBRAF/MEK inhibitorNRNR
 (55)66MNSCLCDKA6 weeks7.6GAD65NRNRYes
56)67FCholangiocarcinomaNRNRNRGAD65Leucovorin, fluorouracil, oxaliplatinNRNR
 (57)58MMelanomaDKA62 days6.8NoneIpilimumabNRNR

*Systemic steroids were used for reasons other than autoimmune diabetes (colitis and adrenal insufficiency); systemic steroids were specifically used for autoimmune diabetes. However, there was no significant improvement or resolution of diabetes; had diagnosis of DM prior of starting nivolumab.

ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP, cyclophosphamide/vincristin/prednisone/procarbazine; DKA, diabetic ketoacidosis; GAD65, glutamic acid decarboxylase 65; IAA, insulin autoantibodies; IA-2, tyrosine phosphatase-related islet antigen 2; ICE, ifosfamide/carboplatin/etoposide; NR, not reported; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer; ZnT8A, zinc transporter 8 autoantibody.

Immunotherapy in general, and nivolumab in specific, has revolutionized cancer therapy, and their use is rapidly growing. Consequently, the number of patients exposed to nivolumab will increase and the total number of patients experiencing AE will expectedly increase (24).

AEs during nivolumab treatment are frequent and range from 40% to 98%. Most commonly, they include fatigue, rash, itching, diarrhea and infusion site reactions. They are largely managed by symptomatic and supportive care (25). The severe AEs (CTCAE grade 3 or 4) are estimated to occur between 5% and 72%.They include pneumonitis, hepatitis and cytopenias. They are typically managed by discontinuing nivolumab and administering systemic corticosteroids (2, 25). Limited data noted suggest treating nivolumab-induced autoimmune DM are unlikely to be effective once DM has developed, and better understanding of why some individuals develop this complication is required before potential therapeutic and even preventative interventions might be identified.

The PD-1 pathway plays a central role in the regulation of autoimmune diabetes (26). Blockade of PD-1 can precipitate type 1 diabetes in mice models across all ages (27) and mechanisms may involve both humoral and cellular autoimmunity (19). However, there remain significant gaps in understanding the interaction between PD-1 pathway and autoimmune diabetes. Sparse data are available regarding the time course, dose relationship, effect of concurrent immunotherapeutic or chemotherapeutic agents and management (e.g. immunomodulatory agents). Despite being an uncommon AE, developing irreversible insulin-dependent DM is life threatening for the patient who presents unexpectedly with DKA. In addition, it has significant socioeconomic impact (28). As the use of anti-PD1 therapy expands, intensivists and hospitalists need to be alerted to the possibility of DKA presenting de novo in patients who are otherwise unlikely to develop type 1 DM.

Declaration of interest

A A Z, H K A, R W J and A S L declare that there is no conflict of interest, proprietary or financial, regarding the publication of this report.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Patient is now deceased and next of kin could not be traced.

Author contribution statement

A A Z was responsible for the literature review and in the primary writing of the manuscript. H K A was the endocrinologist who was involved in the care of the patient’s new diabetes and contributed expertise on the field of drug-induced autoimmune diabetes. R W J was the patient’s primary oncologist and provided expertise on the mechanism of nivolumab and its contribution to autoimmune disorders. A S L was the intensivist in the care of the patient presenting with new-onset diabetic ketoacidosis and provided oversight on the writing and preparation of the manuscript.

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  • 16

    McDermottDFDrakeCGSznol MChoueiriTKPowderlyJDSmithDCBrahmerJRCarvajalRDHammersHJPuzanovI Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. Journal of Clinical Oncology 2015 33 20132020. (https://doi.org/10.1200/JCO.2014.58.1041)

  • 17

    MotzerRJEscudierBMcDermottDFGeorgeSHammersHJSrinivasSTykodiSSSosmanJAProcopioGPlimackER Nivolumab versus everolimus in advanced renal-cell carcinoma. New England Journal of Medicine 2015 373 18031813. (https://doi.org/10.1056/NEJMoa1510665)

  • 18

    AnsellSMLesokhinAMBorrelloIHalwaniAScottECGutierrezMSchusterSJMillensonMMCattryDFreemanGJ PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. New England Journal of Medicine 2015 372 311319. (https://doi.org/10.1056/NEJMoa1411087)

  • 19

    HughesJVudattuNSznolMGettingerSKlugerHLupsaBHeroldKC. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 2015 38 e55e57. (https://doi.org/10.2337/dc14-2349)

  • 20

    AleksovaJLauPKHSoldatosGMcArthurG. Glucocorticoids did not reverse type 1 diabetes mellitus secondary to pembrolizumab in a patient with metastatic melanoma. BMJ Case Reports 2016 2016. (https://doi.org/10.1136/bcr-2016-217454)

  • 21

    ChaeYKChiecLMohindraNGentzlerRPatelJGilesF. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunology Immunotherapy 2017 66 2532. (https://doi.org/10.1007/s00262-016-1913-7)

  • 22

    JørgensenLBYderstrædeK. Acutely induced diabetes mellitus in a 63-year-old female after treatment with ipilimumab for metastatic melanoma. Ugeskrift for Laeger 2017 179 V03170188.

  • 23

    TsiogkaAJanskyGLBauerJWKoelblingerP. Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous melanoma. Melanoma Research 2017 27 524525. (https://doi.org/10.1097/CMR.0000000000000384)

  • 24

    HaanenJBAGvan ThienenHBlankCU. Toxicity patterns with immunomodulating antibodies and their combinations. Seminars in Oncology 2015 42 423428. (https://doi.org/10.1053/j.seminoncol.2015.02.011)

  • 25

    BarbeeMSOgunniyiAHorvatTZDangTO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Annals of Pharmacotherapy 2015 49 907937. (https://doi.org/10.1177/1060028015586218)

  • 26

    AnsariMJISalamaADChitnisTSmithRNYagita HAkibaHYamazakiTAzumaMIwaiHKhourySJ The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. Journal of Experimental Medicine 2003 198 6369. (https://doi.org/10.1084/jem.20022125)

  • 27

    GuleriaIGubbels BuppMDadaSFifeBTangQAnsariMJTrikudanathanSVadivelNFiorinaPYagita H Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clinical Immunology 2007 125 1625. (https://doi.org/10.1016/j.clim.2007.05.013)

  • 28

    GosmanovARGosmanovaEODillard-CannonE. Management of adult diabetic ketoacidosis. Diabetes Metabolic Syndrome and Obesity: Targets and Therapy 2014 7 255264. (https://doi.org/10.2147/DMSO.S50516)

  • 29

    MellatiMEatonKDBrooks-WorrellBMHagopianWAMartinsRPalmerJPHirschIB. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 2015 38 e137e138. (https://doi.org/10.2337/dc15-0889)

  • 30

    MunakataWOhashiKYamauchiNTobinaiK. Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma. International Journal of Hematology 2017 105 383386. (https://doi.org/10.1007/s12185-016-2101-4)

  • 31

    MiyoshiYOgawaOOyamaY. Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku Journal of Experimental Medicine 2016 239 155158. (https://doi.org/10.1620/tjem.239.155)

  • 32

    HofmannLForschnerALoquaiCGoldingerSMZimmerLUgurelSSchmidgenMIGutzmerRUtikalJSGöppnerD Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. European Journal of Cancer 2016 60 190209. (https://doi.org/10.1016/j.ejca.2016.02.025)

  • 33

    OkamotoMOkamotoMGotohKMasakiTOzekiYAndoHAnaiMSatoAYoshidaYUedaS Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. Journal of Diabetes Investigation 2016 7 915918. (https://doi.org/10.1111/jdi.12531)

  • 34

    GauciMLLalyPVidal-TrecanTBaroudjianBGottliebJMadjlessi-EzraNDa MedaLMadelaine-ChambrinIBagotMBasset-SeguinN Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunology Immunotherapy 2017 66 13991410. (https://doi.org/10.1007/s00262-017-2033-8)

  • 35

    TeramotoYNakamuraYAsamiYImamuraTTakahiraSNemotoMSakaiGShimadaANodaMYamamotoA. Case of type 1 diabetes associated with less-dose nivolumab therapy in a melanoma patient. Journal of Dermatology 2017 44 605606. (https://doi.org/10.1111/1346-8138.13486)

  • 36

    IshikawaKShono-SaitoTYamateTKaiYSakaiTShimizuFYamadaYMoriHNosoSIkegamiH A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA and CTLA-4 polymorphisms. European Journal of Dermatology 2017 27 184185. (https://doi.org/10.1684/ejd.2016.2923)

  • 37

    GodwinJLJaggiSSirisenaIShardaPRaoADMehraRVeloskiC. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. Journal for Immunotherapy of Cancer 2017 5 40. (https://doi.org/10.1186/s40425-017-0245-2)

  • 38

    SakuraiKNiitsumaSSatoRTakahashiKAriharaZ. Painless thyroiditis and fulminant type 1 diabetes mellitus in a patient treated with an immune checkpoint inhibitor, nivolumab. Tohoku Journal of Experimental Medicine 2018 244 3340. (https://doi.org/10.1620/tjem.244.33)

  • 39

    AraújoMLigeiroDCostaLMarquesFTrindadeHCorreiaJMFonsecaC. A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. Immunotherapy 2017 9 531535. (https://doi.org/10.2217/imt-2017-0020)

  • 40

    LiLMasoodABariSYavuzSGrosbachAB. Autoimmune diabetes and thyroiditis complicating treatment with nivolumab. Case Reports in Oncology 2017 10 230234. (https://doi.org/10.1159/000456540)

  • 41

    KapkeJShaheenZKilariDKnudsonPWongS. Immune checkpoint inhibitor-associated type 1 diabetes mellitus: case series, review of the literature, and optimal management. Case Reports in Oncology 2017 10 897909. (https://doi.org/10.1159/000480634)

  • 42

    UsuiYUdagawaHMatsumotoSImaiKOhashiKIshibashiMKiritaKUmemuraSYohKNihoS Association of serum anti-GAD antibody and HLA haplotypes with type 1 diabetes mellitus triggered by nivolumab in patients with non-small cell lung cancer. Journal of Thoracic Oncology 2017 12 e41e43. (https://doi.org/10.1016/j.jtho.2016.12.015)

  • 43

    LoweJRPerryDJSalamaAKSMathewsCEMossLGHanksBA. Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. Journal for Immunotherapy of Cancer 2016 4 89. (https://doi.org/10.1186/s40425-016-0196-z)

  • 44

    MarchandLPaulusVFabienNPérolMThivoletCVouillarmetJSaintignyP. Nivolumab-induced acute diabetes mellitus and hypophysitis in a patient with advanced pulmonary pleomorphic carcinoma with a prolonged tumor response. Journal of Thoracic Oncology 2017 12 e182e184. (https://doi.org/10.1016/j.jtho.2017.07.021)

  • 45

    ChangizzadehPNMukkamallaSKRArmenioVA. Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma. Journal for Immunotherapy of Cancer 2017 5 97. (https://doi.org/10.1186/s40425-017-0303-9)

  • 46

    CapitaoRBelloCFonsecaRSaraivaC. New onset diabetes after nivolumab treatment. BMJ Case Reports 2018 2018. (https://doi.org/10.1136/bcr-2017-220999)

  • 47

    VillarrealJTownesDVrablikMRoK. A case of drug-induced severe endocrinopathies: what providers in the emergency department need to know. Advanced Emergency Nursing Journal 2018 40 1620. (https://doi.org/10.1097/TME.0000000000000173)

  • 48

    KumagaiRMuramatsuANakajimaRFujiiMKainoKKatakuraYOkumuraNOharaGKagohashiKSatohH Acute-onset type 1 diabetes mellitus caused by nivolumab in a patient with advanced pulmonary adenocarcinoma. Journal of Diabetes Investigation 2017 8 798799. (https://doi.org/10.1111/jdi.12627)

  • 49

    ChangERiveroGPatelNRChiaoEYLaiSBajajKMbueJEYellapragadaSV. HIV-related refractory Hodgkin lymphoma: a case report of complete response to nivolumab. Clinical Lymphoma Myeloma and Leukemia 2018 18 e143e146. (https://doi.org/10.1016/j.clml.2017.12.008)

  • 50

    Martin-LiberalJFurnessAJJoshiKPeggsKSQuezadaSALarkinJ. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunology Immunotherapy 2015 64 765767. (https://doi.org/10.1007/s00262-015-1689-1)

  • 51

    GaudyCClévyCMonestierSDuboisNPréauYMalletSRichardMAGrobJJValéroRBéliardS. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 2015 38 e182e183. (https://doi.org/10.2337/dc15-1331)

  • 52

    HumayunMAPooleR. A case of multiple immune toxicities from Ipilimumab and pembrolizumab treatment. Hormones 2016 15 303306. (https://doi.org/10.14310/horm.2002.1656)

  • 53

    HansenESahasrabudheDSievertL. A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome. Cancer Immunology Immunotherapy 2016 65 765767. (https://doi.org/10.1007/s00262-016-1835-4)

  • 54

    Mizab MellahCSánchez PérezMSantos ReyMDHernández GarcíaM. Fulminant type 1 diabetes mellitus associated with pembrolizumab. Endocrinologia Diabetes y Nutricion 2017 64 272273. (https://doi.org/10.1016/j.endinu.2017.01.005)

  • 55

    LeonardiGCOxnardGRHaasALangJPWilliamsJSAwadMM. Diabetic ketoacidosis as an immune-related adverse event from pembrolizumab in non-small cell lung cancer. Journal of Immunotherapy 2017 40 249251. (https://doi.org/10.1097/CJI.0000000000000173)

  • 56

    Smith-CohnMAGillDVoorhiesBNAgarwalNGarrido-LagunaI. Case report: pembrolizumab-induced Type 1 diabetes in a patient with metastatic cholangiocarcinoma. Immunotherapy 2017 9 797804. (https://doi.org/10.2217/imt-2017-0042)

  • 57

    ScottESLongGVGuminskiAClifton-BlighRJMenziesAMTsangVH. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. European Journal of Endocrinology 2018 178 175182. (https://doi.org/10.1530/EJE-17-0810)

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Larkin JChiarion-SileniVGonzalezRGrobJJCoweyCLLaoCDSchadendorfDDummerRSmylieMRutkowskiP Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New England Journal of Medicine 2015 373 2334. (https://doi.org/10.1056/NEJMoa1504030)

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RizviNAMazièresJPlanchardDStinchcombeTEDyGKAntoniaSJHornLLenaHMinenzaEMennecierB Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncology 2015 16 257265. (https://doi.org/10.1016/S1470-2045(15)70054-9)

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GettingerSNHornLGandhiLSpigelDRAntoniaSJRizviNAPowderlyJDHeistRSCarvajalRDJackmanDM Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. Journal of Clinical Oncology 2015 33 20042012. (https://doi.org/10.1200/JCO.2014.58.3708)

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BrahmerJReckampKLBaasPCrinò LEberhardtWEEPoddubskaya EAntoniaSPluzanskiAVokesEEHolgadoE Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New England Journal of Medicine 2015 373 123135. (https://doi.org/10.1056/NEJMoa1504627)

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BorghaeiHPaz-AresLHornLSpigelDRSteinsMReadyNEChowLQVokesEEFelipEHolgadoE Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. New England Journal of Medicine 2015 373 16271639. (https://doi.org/10.1056/NEJMoa1507643)

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McDermottDFDrakeCGSznol MChoueiriTKPowderlyJDSmithDCBrahmerJRCarvajalRDHammersHJPuzanovI Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. Journal of Clinical Oncology 2015 33 20132020. (https://doi.org/10.1200/JCO.2014.58.1041)

17

MotzerRJEscudierBMcDermottDFGeorgeSHammersHJSrinivasSTykodiSSSosmanJAProcopioGPlimackER Nivolumab versus everolimus in advanced renal-cell carcinoma. New England Journal of Medicine 2015 373 18031813. (https://doi.org/10.1056/NEJMoa1510665)

18

AnsellSMLesokhinAMBorrelloIHalwaniAScottECGutierrezMSchusterSJMillensonMMCattryDFreemanGJ PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. New England Journal of Medicine 2015 372 311319. (https://doi.org/10.1056/NEJMoa1411087)

19

HughesJVudattuNSznolMGettingerSKlugerHLupsaBHeroldKC. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 2015 38 e55e57. (https://doi.org/10.2337/dc14-2349)

20

AleksovaJLauPKHSoldatosGMcArthurG. Glucocorticoids did not reverse type 1 diabetes mellitus secondary to pembrolizumab in a patient with metastatic melanoma. BMJ Case Reports 2016 2016. (https://doi.org/10.1136/bcr-2016-217454)

21

ChaeYKChiecLMohindraNGentzlerRPatelJGilesF. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunology Immunotherapy 2017 66 2532. (https://doi.org/10.1007/s00262-016-1913-7)

22

JørgensenLBYderstrædeK. Acutely induced diabetes mellitus in a 63-year-old female after treatment with ipilimumab for metastatic melanoma. Ugeskrift for Laeger 2017 179 V03170188.

23

TsiogkaAJanskyGLBauerJWKoelblingerP. Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous melanoma. Melanoma Research 2017 27 524525. (https://doi.org/10.1097/CMR.0000000000000384)

24

HaanenJBAGvan ThienenHBlankCU. Toxicity patterns with immunomodulating antibodies and their combinations. Seminars in Oncology 2015 42 423428. (https://doi.org/10.1053/j.seminoncol.2015.02.011)

25

BarbeeMSOgunniyiAHorvatTZDangTO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Annals of Pharmacotherapy 2015 49 907937. (https://doi.org/10.1177/1060028015586218)

26

AnsariMJISalamaADChitnisTSmithRNYagita HAkibaHYamazakiTAzumaMIwaiHKhourySJ The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. Journal of Experimental Medicine 2003 198 6369. (https://doi.org/10.1084/jem.20022125)

27

GuleriaIGubbels BuppMDadaSFifeBTangQAnsariMJTrikudanathanSVadivelNFiorinaPYagita H Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clinical Immunology 2007 125 1625. (https://doi.org/10.1016/j.clim.2007.05.013)

28

GosmanovARGosmanovaEODillard-CannonE. Management of adult diabetic ketoacidosis. Diabetes Metabolic Syndrome and Obesity: Targets and Therapy 2014 7 255264. (https://doi.org/10.2147/DMSO.S50516)

29

MellatiMEatonKDBrooks-WorrellBMHagopianWAMartinsRPalmerJPHirschIB. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 2015 38 e137e138. (https://doi.org/10.2337/dc15-0889)

30

MunakataWOhashiKYamauchiNTobinaiK. Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma. International Journal of Hematology 2017 105 383386. (https://doi.org/10.1007/s12185-016-2101-4)

31

MiyoshiYOgawaOOyamaY. Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku Journal of Experimental Medicine 2016 239 155158. (https://doi.org/10.1620/tjem.239.155)

32

HofmannLForschnerALoquaiCGoldingerSMZimmerLUgurelSSchmidgenMIGutzmerRUtikalJSGöppnerD Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. European Journal of Cancer 2016 60 190209. (https://doi.org/10.1016/j.ejca.2016.02.025)

33

OkamotoMOkamotoMGotohKMasakiTOzekiYAndoHAnaiMSatoAYoshidaYUedaS Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. Journal of Diabetes Investigation 2016 7 915918. (https://doi.org/10.1111/jdi.12531)

34

GauciMLLalyPVidal-TrecanTBaroudjianBGottliebJMadjlessi-EzraNDa MedaLMadelaine-ChambrinIBagotMBasset-SeguinN Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunology Immunotherapy 2017 66 13991410. (https://doi.org/10.1007/s00262-017-2033-8)

35

TeramotoYNakamuraYAsamiYImamuraTTakahiraSNemotoMSakaiGShimadaANodaMYamamotoA. Case of type 1 diabetes associated with less-dose nivolumab therapy in a melanoma patient. Journal of Dermatology 2017 44 605606. (https://doi.org/10.1111/1346-8138.13486)

36

IshikawaKShono-SaitoTYamateTKaiYSakaiTShimizuFYamadaYMoriHNosoSIkegamiH A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA and CTLA-4 polymorphisms. European Journal of Dermatology 2017 27 184185. (https://doi.org/10.1684/ejd.2016.2923)

37

GodwinJLJaggiSSirisenaIShardaPRaoADMehraRVeloskiC. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. Journal for Immunotherapy of Cancer 2017 5 40. (https://doi.org/10.1186/s40425-017-0245-2)

38

SakuraiKNiitsumaSSatoRTakahashiKAriharaZ. Painless thyroiditis and fulminant type 1 diabetes mellitus in a patient treated with an immune checkpoint inhibitor, nivolumab. Tohoku Journal of Experimental Medicine 2018 244 3340. (https://doi.org/10.1620/tjem.244.33)

39

AraújoMLigeiroDCostaLMarquesFTrindadeHCorreiaJMFonsecaC. A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. Immunotherapy 2017 9 531535. (https://doi.org/10.2217/imt-2017-0020)

40

LiLMasoodABariSYavuzSGrosbachAB. Autoimmune diabetes and thyroiditis complicating treatment with nivolumab. Case Reports in Oncology 2017 10 230234. (https://doi.org/10.1159/000456540)

41

KapkeJShaheenZKilariDKnudsonPWongS. Immune checkpoint inhibitor-associated type 1 diabetes mellitus: case series, review of the literature, and optimal management. Case Reports in Oncology 2017 10 897909. (https://doi.org/10.1159/000480634)

42

UsuiYUdagawaHMatsumotoSImaiKOhashiKIshibashiMKiritaKUmemuraSYohKNihoS Association of serum anti-GAD antibody and HLA haplotypes with type 1 diabetes mellitus triggered by nivolumab in patients with non-small cell lung cancer. Journal of Thoracic Oncology 2017 12 e41e43. (https://doi.org/10.1016/j.jtho.2016.12.015)

43

LoweJRPerryDJSalamaAKSMathewsCEMossLGHanksBA. Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. Journal for Immunotherapy of Cancer 2016 4 89. (https://doi.org/10.1186/s40425-016-0196-z)

44

MarchandLPaulusVFabienNPérolMThivoletCVouillarmetJSaintignyP. Nivolumab-induced acute diabetes mellitus and hypophysitis in a patient with advanced pulmonary pleomorphic carcinoma with a prolonged tumor response. Journal of Thoracic Oncology 2017 12 e182e184. (https://doi.org/10.1016/j.jtho.2017.07.021)

45

ChangizzadehPNMukkamallaSKRArmenioVA. Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma. Journal for Immunotherapy of Cancer 2017 5 97. (https://doi.org/10.1186/s40425-017-0303-9)

46

CapitaoRBelloCFonsecaRSaraivaC. New onset diabetes after nivolumab treatment. BMJ Case Reports 2018 2018. (https://doi.org/10.1136/bcr-2017-220999)

47

VillarrealJTownesDVrablikMRoK. A case of drug-induced severe endocrinopathies: what providers in the emergency department need to know. Advanced Emergency Nursing Journal 2018 40 1620. (https://doi.org/10.1097/TME.0000000000000173)

48

KumagaiRMuramatsuANakajimaRFujiiMKainoKKatakuraYOkumuraNOharaGKagohashiKSatohH Acute-onset type 1 diabetes mellitus caused by nivolumab in a patient with advanced pulmonary adenocarcinoma. Journal of Diabetes Investigation 2017 8 798799. (https://doi.org/10.1111/jdi.12627)

49

ChangERiveroGPatelNRChiaoEYLaiSBajajKMbueJEYellapragadaSV. HIV-related refractory Hodgkin lymphoma: a case report of complete response to nivolumab. Clinical Lymphoma Myeloma and Leukemia 2018 18 e143e146. (https://doi.org/10.1016/j.clml.2017.12.008)

50

Martin-LiberalJFurnessAJJoshiKPeggsKSQuezadaSALarkinJ. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunology Immunotherapy 2015 64 765767. (https://doi.org/10.1007/s00262-015-1689-1)

51

GaudyCClévyCMonestierSDuboisNPréauYMalletSRichardMAGrobJJValéroRBéliardS. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 2015 38 e182e183. (https://doi.org/10.2337/dc15-1331)

52

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