Sintilimab-induced autoimmune diabetes: A case report and review of the literature

Table 1 Laboratory data at presentation

Admission bloods (normal range, units)	Results
BMI (kg/m2)	18.8
Finger prick glucose (mmol/L)	23.4
urinary glucose	++++
Ketones (mmol/L)	Negative
HbA1c [4%–6% (20–42 mmol/mol)]	8.2%
C-peptide (1.0–7.1 ng/mL)	0.22
Testosterone (0.1–1.1 ng/mL)	0.18
Progesterone (0.00–0.20 ng/mL)	< 1.0
Estradiol (10.00–28.00 pg/mL)	< 10
FSH (26.70–133.40 IU/L)	45.52
LH (5.20–62.0 IU/L)	18.55
Prolactin (5.20–26.50 ng/mL)	9.13
8 am ACTH (0.00-46.00 pg/mL)	15.90
8 am cortisol (67.00-226.00 µg/L)	113.00
ARR (≤ 150 pg/mL)	2.53
TSH (15.00–65.00 mIU/L)	0.98
TT3 (0.66–1.61ug/L)	1.03
TT4 (54.40–118.50 ug/L)	116.86
FT3 (1.0–7.1 ng/L)	3.35
FT4 (1.0–7.1 ng/L)	6.00
ATG (<4.00 IU/L)	17.80
TPO (<9.00 IU/L)	10.00
GAD	Negative
ICA	Negative
IAA	Negative
ZnT8	Negative
IL-2 (0.00–4.10 pg/mL)	0.04
IL-4 (0.10-3.20 pg/mL)	0.01
IL-6 (0.00–5.00 pg/mL)	0.00
IL-10 (0.00–5.90 pg/mL	0.13
TNF-α (0.00–6.00 pg/mL)	0.81
IFN-γ (0.00–6.00 pg/mL	1.36
IL-17A (0.00–5.90 pg/mL)	0.70

BMI: Body mass index; TSH: Thyroid-stimulating hormone; FT4: Free thyroxine; FT3: Free triiodothyronine; TT4: Total thyroxine; TT3: Total triiodothyronine; PTH: Parathyroid hormone; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; ACTH: Adrenocorticotropic hormone; HGH: Human growth hormone; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; IFN-γ: Interferon gamma; ATG: Anti-thyroglobulin antibodies; TPO: Thyroid peroxidases antibody; GAD: Anti-glutamic acid decarboxylase 65; ICA: Anti-islet cell antibody; IAA: Anti-insulin antibody; ZnT8: Zinc transporter8 antibody; ARR: Aldosterone/renin ratio.

Table 2 High-resolution genotyping of human leukocyte antigen class I and II of patient with diabetes induced by immune checkpoint inhibitor

HLA type	A	B	C	DRB1	DQB1	DPB1
Alleles	02:01	35:03	04:01	04:01	03:01	02:01
	24:02	51:05	14:02	14:03	03:02	02:01

HLA: Human leukocyte antigen.

Table 3 Reported cases of diabetes induced by immune checkpoint inhibitors

Ref.	Sex/ Age (yr)	Primary diagnosis	Relevant history	Anti-PD-1/Anti-PD-L1 drug	Other chemo-therapies	Presentation	Other side effects	HbA1c	C peptide	Antibodies	Time with anti-PD-1 (w)	HLA
Araújo et al[6], 2017	F/73	NSCLC	N	Nivolumab	Carboplatin +pemetrexed	DKA	N	7.20%	0.06 ng/ml	GAD+	5	High risk: DR3-DQ2/DR4-DQ8
Li et al[7], 2020	M/73	NSCLC	N	Nivolumab	Sunitinib	DKA	N	10.90%	0.24 ng/mL	-	30	Unavailable
Abdullah et al[8], 2019	M/68	Melanoma	N	Nivolumab	None	DKA	N	Unavailable	0.1 ng/mL	-	4	Unavailable
Kapke et al[9], 2017	M/83	Oral squamous cell carcinoma	Hypothyroidism	Nivolumab	None	DKA	N	Unavailable	0.32 ng/mL	GAD+	12	High risk: DRB1*08, DRB1*11, DQB1*03, DQB1*04, DQA1*04, and DQA1*05.
Kapke et al[9], 2017	F/63	Urothelial carcinoma of the bladder	Hypothyroidism	Atezolizumab	Gemcitabine + cisplatin	DKA	N	Unavailable	0.02 ng/mL	GAD+	6	High risk: DRB1*03, DRB1*04, DQB1*02, DQB1*03,DQA1*03, and DQA1*05.
Lowe et al[10], 2016	M/54	Melanoma	N	Nivolumab +ipilimumab	None	DKA	Autoimmune, thyroiditis	Unavailable	< 0.1 ng /mL	GAD+	19	Unavailable
Rahman et al[11], 2020	M/64	Renal cell carcinoma	T2DM	Atezolizumab	Bevacizumab	DKA	N	Unavailable	Unavailable	GAD+	12	Unavailable
Mengíbar et al[12], 2019	M/55	Urothelial carcinoma of the bladder	Family history of T1D	Durvalumab	None	DKA	Hypothyroidism	8.40%	0.02 ng/mL	GAD+, IA2+	3	Unavailable
Kichloo et al[13], 2020	F/77	Colonic adenocarcinoma	N	Pembrolizumab	FOLFOX (leucovorin, fluorouracil, oxaliplatin	DKA	N	8.80%	Unavailable	-	44	Unavailable
Delasos et al[14], 2020	M/77	Neuroendocrine tumor	N	Nivolumab	Carboplatin + etoposide	DKA	N	8.30%	Unavailable	-	28	Unavailable
Hickmott et al[15], 2017	M/57	Urothelial cancer	N	Atezolizumab	Cisplatin + gemcitabine	DKA	N	7.50%	0.65 ng/mL	-	15	High risk: DRB1*11, DRB1*04; DRB3*02; DRB4*01; DQB1*03, DQB1*03
Sothornwit et al[16], 2017	F/52	NSCLC	N	Atezolizumab	None	DKA	Transaminitis	7.90%	0.1 ng/ml	GAD+	24	DRB1∗03, DRB1∗14, DQB1∗02, DQB1∗05 (DR3-DQ2/DR14-DQ5)
Changizzadeh et al[17], 2019	M/44	Melanoma	N	Nivolumab + ipilimumab	None	DKA	N	6.50%	Unavailable	-	12	Unavailable
Gunawan et al[18], 2018	M/52	Melanoma	N	Nivolumab + ipilimumab	None	hyperglycemia Ketonuria	Hypophysitis, thyroiditis, adrenal inefficiency	7.70%	0.05 nmol/L (0.016 ng/ml)	-	3	Unavailable
Gunjur et al[19], 2019	F/77	Melanoma	N	Pembrolizumab	None	DKA	Thyroidits	6.9% (normal range: <6.5%)	0.07 ng/ml	GAD+,IA2+	3	DRB1*04:16, DQB1*02:05 and DQA1*01:03
Atkins et al[20], 2018	M/50	Squamous cell carcinoma of the tonsil	N	Avelumab	Utomilumab	DKA	N	6.40%	63 pmol/L	GAD+	4	Unavailable
Marchand et al[21], 2019	F/65	Melanoma	N	Nivolumab + ipilimumab	None	DKA	Hypereosinophilia	7.30%	<0.1 ng/mL	-	12	DRB1*01:01 DQA1*01DQB1*03:01 DRB1*11:01 DQA1*05 DQB1*05:01
Tzoulis et al[22], 2018	F/56	NSCLC	N	Nivolumab	Pemetrexed + cisplatin	DKA	N	8.20%	Undetectable	GAD+	7	Unavailable
Porntharukchareon et al[23], 2020	M/70	NSCLC	N	Pembrolizumab + ipilimumab	None	DKA	IAD	6.50%	< 0.1 ng/ml	-	14	Unavailable
Lee et al[24], 2020	M/67	NSCLC	T2DM	Nivolumab	Carboplatin + paclitaxel	DKA	Thyroiditis	7.60%	<0.1 ng/mL	GAD+	2	Unavailable
Leonardi et al[25], 2017	M/66	NSCLC	N	Pembrolizumab	None	hyperglycemia Ketonuria	N	7.6% (4.2%–5.8%)	0.3 ng/mL	GAD+	12	Unavailable
Wong et al[26], 2020	F/55	Squamous cell lung carcinoma.	N	Atezolizumab	None	hyperglycemia Ketonuria	N	Unavailable	0.6nmol/L (0.19 ng/ml)	ZnT8+	8	Unavailable
Chokr et al[27], 2018	F/61	Melanoma	N	Nivolumab + ipilimumab,	None	DKA	N	6.90%	<0.1 ng/ml.	-	9	Unavailable
Chan et al[28], 2017	M/74	Melanoma	N	Nivolumab + ipilimumab	None	DKA	Transaminitis	Unavailable	Unavailable	-	14	Unavailable
Zezza et al[29], 2019	F/60	Melanoma	T2DM	Nivolumab + ipilimumab	None	DKA	N	7.60%	Unavailable	GAD+ICA+, IA2+	2	Unavailable
Zezza et al[29], 2019	F/80	Melanoma	N	Nivolumab + ipilimumab	None	DKA	Thyroiditis	Unavailable	Unavailable	GAD+	3	Unavailable
Shibayama et al[30], 2019	F/79	Merkel cell carcinoma	N	Avelumab	None	Hyperglycemia Ketonuria	N	7.50%	<0.1 ng/mL	-	20	High risk: DRB1 *09:01:02 DRB1 *14:54:01 DQA1 *01:04 DQA1 *03:02 DQB1 *05:02:01 and DQB1 *03:03:02
Marchand et al[21], 2019	M/65	Melanoma	N	Nivolumab	None	DKA	Hashimoto	8.5% (74 mmol/mol)	<0.1 ng/mL	-	34	High risk: DRB1*04:01 DQA1*02 DQB1*02:02 DRB1*07:01 DQA1*03 DQB1*03:01
Okamoto et al[31], 2016	F/55	Melanoma	N	Nivolumab	Acarbazine, + nimustine, + cisplatin + tamoxifen	Hyperglycemia Ketonuria	N	7.00%	1.0 ng/mL	-	48	High risk: DRB1*04:05-DQB1*04:01
Godwin et al[32], 2017	F/34	NSCLC	N	Nivolumab	Carboplatin + pemetrexed	DKA	N	7.1% (normal range 4.6–6.1%)	<0.1 ng/mL	GAD+, IA2+ ZnT8+	3	A30:01, 30:02 (A30) D09:CTZ, 09:CTZ (DR9)
Smith-Cohn et al[33], 2017	F/66	Cholangiocarcinoma	N	Pembrolizumab	None	Hyperglycemia	N	8.7% (4.2%–5.8%)	Unavailable	GAD+	12	Unavailable
Marchand et al[21], 2019	M/83	Melanoma	N	Pembrolizumab	None	Hyperglycemia	Hashimoto’s disease	9.40%	1.0 ng/mL	-	12	DRB1*01:01 DQA1*01 DQB1*05:01/ DRB1*16:01 DQA1*01 DQB1*05:02
Maamari et al[34], 2019-3	F/47	Cardiac angiosarcoma	N	Pembrolizumab	Ifosfamide, gemcitabine, docetaxel	DKA	N	6.40%	0.1 ng/mL	GAD+	3	Unavailable
Tassone et al[35], 2019-9	M/42	Pulmonary adenocarcinoma	N	Nivolumab	None	DKA	N	Unavailable	0.2 ng/dL (2ng/ml)	GAD+	12	DRB1*03:15-DQB1*02:06
Yilmas et al[36], 2020-8	M/49	Renal cell carcinoma	N	Nivolumab	None	DKA	N	10.90%	2.4 ng/mL	-	44	Unavailable
Wen et al[37], 2020	M/56	Hepatocellular carcinoma	N	Sintilimab	None	DKA	N	7.80%	1.12 ng/mL	-	24	DRB1*12:01 DRB1*12:02; DQB1 *05:03 DQB1 *03:01; DQA1 *01:04 DQA1 *06:01

T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; GAD: Anti-glutamic acid decarboxylase antibody; HLA: Human leukocyte antigen; irAE: Immune-related adverse effect; SCLC: Small cell lung cancer; NSCLC: Non-small cell lung cancer; DKA: Diabetic ketoacidosis; Ad: Adenocarcinoma; IAD: Isolated adrenocorticotropic hormone deficiency; N: None.

Table 4 Characteristics of patients with diabetes induced by immune checkpoint inhibitors

Reported cases	n (%)
Tumor types
Melanoma	13/36 (36.1)
NSCLC	8/36 (22.2)
Renal cell carcinoma	2/36 (5.6)
Squamous cell carcinoma	3/36 (8.3)
Other cancers	10/36 (27.8)
ICBs
Anti PD-1	19/ 36 (52.7)
Nivolumab	12
Pembrolizumab	6
Sintilimab	1
Anti PD-L1	8/ 36 (22.2)
Avelumab	2
Atezolizumab	5
Durvalumab	1
Anti PD-1+CTLA-4	9/ 36 (25.0)
Nivolumab + ipilimumab	8
Pembrolizumab + ipilimumab	1
Demographic data
Sex (F/M)	16/20
Average age (yr)	58.8
Time of diagnosis after start of (w)	14.6
Presentation
DKA	29/36 (80.6)
Hyperglycemia Ketonuria	8/36 (22.2)
HbA1c, % (avg)	7.8 26/36
Relevant history
T2DM	3/36 (8.3)
Hypothyroidism	2/36 (5)
Family history of T1DM	2/36 (5)
None	29/36 (80.5)
Antibodies
GAD+	18/36 (50)
IA-2+	4/36 (10)
ZnT8+	2/36 (5)
Negative	12/36 (33.3)

NSCLC: Non-small cell lung cancer; PD-L1: Programmed death-ligand 1; DKA: Diabetic ketoacidosis; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; GAD: Anti-glutamic acid decarboxylase antibody.