doi:10.1507/endocrj.EJ19-0163
Opinion

Management of immune-related adverse events in

endocrine organs induced by immune checkpoint
inhibitors: clinical guidelines of the Japan Endocrine
Society
Hiroshi Arima1), Shintaro Iwama2), Hidefumi Inaba3), Hiroyuki Ariyasu3), Noriko Makita4), Michio Otsuki5),
Kazunori Kageyama6), Akihisa Imagawa7) and Takashi Akamizu3)

1)
Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
2)
Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya 466-8560, Japan
3)
The First Department of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
4)
Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan
5)
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
6)
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
7)
Department of Internal Medicine (I), Osaka Medical College, Takatsuki 569-8686, Japan

Abstract. Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However,
these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver,
muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid
dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening
consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important
that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them
appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes
Society for the management of endocrine irAEs induced by ICIs.

Key words: Hypopituitarism, Adrenal insufficiency, Thyroid dysfunction, Hypoparathyroidism, Diabetes

Introduction in several tissues such as skin, gastrointestinal tract,

Immune checkpoint inhibitors (ICIs) are monoclonal
antibodies against cytotoxic T lymphocyte antigen-4
(CTLA-4), programmed cell death (PD)-1, and its ligand
(PD-L1) that have been approved as anti-cancer drugs
and are used widely as promising treatment for several
advanced malignancies (Table 1). The ICIs have promi‐
nent anti-tumor effects which are considered to be medi‐
ated via activation of immune systems. However, ICIs
may also cause immune-related adverse events (irAEs)
Submitted Apr. 24, 2019; Accepted May 30, 2019 as EJ19-0163
Released online in J-STAGE as advance publication Jun. 25, 2019
Correspondence to: Hiroshi Arima, Department of Endocrinology
and Diabetes, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
E-mail: arima105@med.nagoya-u.ac.jp
Correspondence to: Takashi Akamizu, The First Department of
Medicine, Wakayama Medical University, 811-1 Kimiidera,
Wakayama, Wakayama 641-8509, Japan.
E-mail: akamizu@wakayama-med.ac.jp
liver, lung, muscle, nerve and endocrine organs [1]. The
endocrine irAEs include hypopituitarism, primary adre‐
nal insufficiency, thyroid dysfunction, hypoparathyroid‐
ism, and type 1 diabetes mellitus [2]. Symptoms caused
by endocrine irAEs such as fatigue, appetite loss, and
weight loss are frequently observed in patients with
malignancies, and attending physicians may therefore
overlook endocrine irAEs in clinical practice if they are
not aware of them. In order to avoid serious outcomes it
is therefore important that endocrinologists and oncolo‐
gists understand possible endocrine irAEs induced by
ICIs.
In 2018, the American Society of Clinical Oncology
[3] and the Society for Endocrinology in the UK [4] both
published guidelines for the management of endocrine
irAEs induced by ICIs. The Japan Endocrine Society
also published the Japanese version of the guidelines in
the same year [5]. This opinion paper reports the updated
English version of these guidelines.

©The Japan Endocrine Society

2 Arima et al.
Table 1 Immune checkpoint inhibitors approved in Japan
Class Anti-CTLA-4 antibody
Ipilimumab
CTLA-4, cytotoxic T lymphocyte antigen-4; PD-1, programmed cell death-1; PD-L1, a ligand of PD-1
Summary of Recommendations
Hypopituitarism
Overview
The incidence of hypopituitarism associated with anti-
CTLA-4 or anti-PD-1 antibody treatment is reported to
be around 10% or <1%, respectively [6-11]. For anti-
CTLA-4 antibodies, hypopituitarism develops in most
cases approximately 10 weeks after the start of treatment
[6]. In contrast, the duration from initiation of treatment
with anti-PD-1 or anti-PD-L1 antibodies to the onset of
hypopituitarism can be longer, up to several months or
even a year [12-14]. Hypopituitarism induced by ICIs
can develop even after the withdrawal of the drugs.
Given the functional mechanisms of these drugs and the
fact that the clinical features such as the enlargement of
the pituitary gland and/or a stalk are similar to those seen
in patients with autoimmune hypophysitis, it is possible
that hypopituitarism induced by ICIs results from inflam‐
mation of the pituitary glands. Deficiency of adrenocorti‐
cotropic hormone (ACTH) secretion is observed in
almost all patients who develop hypopituitarism induced
by ICIs [6]. While TSH and/or gonadotropin deficiency
is often accompanied by ACTH deficiency in patients
treated with anti-CTLA-4 antibodies, almost all patients
who develop pituitary dysfunction with anti-PD-1 or
anti-PD-L1 antibodies show isolated ACTH deficiency
[15]. Central diabetes insipidus is rarely induced by ICIs
[6].
Symptoms
The symptoms of hypopituitarism induced by ICIs
include tiredness, weakness, anorexia, weight loss,
digestive symptoms (nausea, vomiting, and diarrhea),
decreased blood pressure, psychiatric disturbance (apa‐
thy, anxiety, and depression), fever, hypoglycemic symp‐
toms, joint pain, headache, or visual field disturbance.
Testing
Laboratory data show decreased levels of hormones
secreted by the pituitary and the targeted organs.
Additional findings
MRI of the pituitary shows enlargement of the pitui‐
tary gland and/or a stalk with gadolinium-enhancement
in some patients.
Endocrine Journal Advance Publication
Anti-PD-1 antibody Anti-PD-L1 antibody
Nivolumab Atezolizumab
Pembrolizumab Avelumab
Durvalumab
Diagnosis
Hypopituitarism induced by ICIs is diagnosed based
on findings of decreased basal levels of hormones secre‐
ted by the pituitary and targeted organs, or decreased
responses of pituitary hormones in loading tests.
Treatment
Hydrocortisone (10–20 mg/day) should be adminis‐
tered for ACTH deficiency. High doses of glucocorti‐
coids are not recommended because there is no evidence
that the use could improve the pituitary function or the
survival outcomes [16, 17]. However, glucocorticoids
can be administered to patients with marked enlargement
of the pituitary gland accompanied by headaches and
disturbances of vision or the visual field. In such cases,
reference doses of glucocorticoids are those used for
patients with autoimmune hypophysitis (e.g. 0.5–1.0
mg/kg/day of predonisolone).
In cases of adrenal crisis, the treatment should be
referred to the guideline [18].
If patients have both ACTH and TSH deficiency,
hydrocortisone must be administered before starting thy‐
roid hormone replacement. It is recommended to start
administration of levothyroxine at low doses (12.5–25
μg/day) 5–7 days after the administration of hydrocorti‐
sone, with the dose adjusted according to the serum level
of FT4.
The use of ICIs in patients with hypopituitarism
should be withheld until the general conditions are stabi‐
lized by treatment.
Primary adrenal insufficiency
Overview
While primary adrenal insufficiency induced by ICIs
may result from inflammation in the adrenal glands, the
number of cases reported to date is small and there is no
histological evidence showing the presence of inflamma‐
tion in the adrenal glands. Case reports showed that
primary adrenal insufficiency developed 10 weeks after
initiation of anti-PD-1 antibody treatment [19] and 16
weeks after initiation of anti-CTLA-4 antibody treatment
[20]. A systematic review has reported that the incidence
was 0.7% (43 of 5,871) [9], although this may be an
underestimate due to the use of glucocorticoids as cancer
therapy or concomitant secondary adrenal insufficiency
 Guidelines for endocrine irAEs
caused by hypopituitarism.
Symptoms
The symptoms of primary adrenal insufficiency
induced by ICIs include general fatigue, tiredness, weak‐
ness, loss of muscle strength, weight loss, anorexia,
digestive symptoms (nausea, vomiting, and diarrhea),
psychiatric symptoms (apathy, anxiety, and depression),
impaired consciousness, or decreased blood pressure.
Testing
Laboratory data shows decreased levels of serum cor‐
tisol with normal or increased levels of plasma ACTH,
increased levels of plasma renin activity (or renin con‐
centration), hyponatremia, hyperkalemia, or hypoglyce‐
mia.
Additional findings
It has been reported that PET scans showed bilateral
increased uptake of FDG in adrenal glands [19], while
abdominal CT showed bilateral enlargement of the adre‐
nal glands [20]. However, it should be noted that these
findings can also be observed in primary or metastatic
cancer of adrenal glands.
Diagnosis
Primary adrenal insufficiency induced by ICIs is diag‐
nosed based on data of decreased levels of serum cortisol
with normal or increased levels of plasma ACTH, a
decreased response of cortisol secretion in the ACTH
stimulation test, and the presence of ACTH secretion in
response to corticotropin-releasing hormone.
Treatment
Hydrocortisone (10–20 mg/day) should be adminis‐
tered for cortisol deficiency without delay [18]. High
doses of glucocorticoids are not recommended because
there is no evidence to support their use for primary
adrenal insufficiency. In cases of adrenal crisis, treatment
should be in accordance with the guidelines for adrenal
crisis. Fludrocortisone (0.05–0.2 mg/day) can be admin‐
istered in combination with hydrocortisone if patients
show hyponatremia, hypotension, or salt-wasting symp‐
toms.
The use of ICIs in patients with primary adrenal insuf‐
ficiency should be withheld until the general conditions
are stabilized by treatment.
Thyroid dysfunction
Overview
The incidence of thyroid dysfunction following treat‐
ment with anti-PD-1 antibodies is reported to be 5–10%,
which is higher than that observed with anti-CTLA-4
antibodies (0–5%) [8-10]. Treatment with anti-PD-L1
antibodies also leads to thyroid dysfunction (0–5%)
[8-10]. Low T3 syndrome, often seen in patients with
advanced malignancies, should be differentiated. Thy‐
roid dysfunction induced by ICIs is classified into thyro‐
Endocrine Journal Advance Publication
3
toxicosis and hypothyroidism. Thyrotoxicosis develops
2–6 weeks after the administration of ICIs in most cases,
and is often followed by the development of hypothy‐
roidism [21]. It is possible that activation of pre-existing
autoimmunity against thyroid glands is involved in the
pathogenesis of thyroid dysfunction induced by ICIs. For
example, the incidence of thyroid dysfunction is report‐
edly higher in patients who have anti-thyroglobulin anti‐
bodies (TgAb) and/or anti-thyroid peroxidase antibodies
(TPOAb) prior to the initiation of the treatment with
nivolumab than in patients without these antibodies [22,
23].
Symptoms
1) The symptoms of thyrotoxicosis induced by ICIs
include palpitations, sweating, fever, diarrhea, tremor,
weight loss, or general fatigue.
2) The symptoms of hypothyroidism induced by ICIs
include general fatigue, anorexia, constipation, brady‐
cardia, or weight gain.
Testing and diagnosis
1) Thyrotoxicosis induced by ICIs is diagnosed based on
suppressed levels of serum TSH and elevated levels of
serum FT4 and/or FT3. Anti-TSH receptor antibodies
are rarely positive.
2) Hypothyroidism induced by ICIs is diagnosed based
on increased levels of serum TSH and low levels of
serum FT4 and/or FT3.
In most cases of thyroid dysfunction induced by ICIs,
thyroid ultrasonography shows diffuse enlargement of
the thyroid gland accompanied by decreased internal
blood flow and low internal echogenicity, while thyroid
scintigraphy shows decreased uptake of isotope, sugges‐
tive of destructive thyroiditis.
Treatments
1) Thyrotoxicosis
β blockers (e.g. propranolol 30 mg/day) is effective for
relieving symptoms. In cases of Graves’ disease treat‐
ment with anti-thyroid drugs should be considered.
2) Hypothyroidism
Administration of levothyroxine is started at 25–50
μg/day (12.5 μg/day in elderly or patients with cardiac
diseases), with the dose adjusted according to serum
TSH levels. It is unclear whether thyroid function may
recover or not. Effectivity of high doses of glucocorti‐
coids for thyroid dysfunction is also unclear.
The use of ICIs in patients with thyroid dysfunction
should be withheld until the general conditions are stabi‐
lized by treatment.
Hypoparathyroidism
Overview
While it is possible that hypoparathyroidism induced
by ICIs results from inflammation in the parathyroid
4 Arima et al.
glands, the number of cases reported to date is small and
there is no histological evidence showing the presence of
such inflammation. There is evidence that patients trea‐
ted with an anti-PD-1 antibody alone or in combination
with anti-CTLA-4 antibodies developed hypoparathy‐
roidism 1–4 months after the initiation of the drugs
[24-27]. Because serum calcium levels can be affected
by advanced malignancies per se or by treatment, evalu‐
ation of serum calcium levels, intact PTH, 25-OH vita‐
min D, phosphorus, and magnesium, as well as urinary
excretion of calcium and magnesium should be per‐
formed for differential diagnosis.
Symptoms
The symptoms of acute hypocalcemia due to hypopar‐
athyroidism induced by ICIs are neuromuscular symp‐
toms (numbness in the limbs or tetany) or convulsions.
Testing and diagnosis
Hypoparathyroidism induced by ICIs is diagnosed
based on decreased levels of serum intact PTH, hypocal‐
cemia, and hyperphosphatemia.
Additional findings
Hypocalcemia associated with hypomagnesemia
should be diagnosed differentially. It is possible that
increased bone absorption due to thyrotoxicosis induced
by ICIs may mask hypocalcemia due to hypoparathy‐
roidism.
Treatment
Calcium gluconate should be administered intrave‐
nously to urgently treat patients with symptoms associ‐
ated with hypocalcemia [e.g. intravenous injection of
8.5% calcium gluconate (10–20 mL) for 10–20 min, fol‐
lowed by injection at the rate of 2–4 mL/hr]. In patients
who do not require emergency medical care, administra‐
tion of active vitamin D is started (e.g. 1–3 μg/day of
alfacalcidol). In chronic phase, to prevent urinary stones
and kidney dysfunction the dose of active vitamin D
should be adjusted so that serum calcium levels are kept
in the range of 7.5–8.5 mg/dL and urine calcium/creati‐
nine ratio <0.3. In most cases, supplementation with cal‐
cium is not necessary.
The use of ICIs in patients with hypoparathyroidism
should be withheld until the general conditions are stabi‐
lized by treatment.
Type 1 diabetes mellitus [28]
Overview
Although the incidence of type 1 diabetes mellitus
induced by ICIs is <1%, it has been reported that treat‐
ment with anti-PD-1 antibodies is more likely to induce
type 1 diabetes mellitus than treatment with anti-
CTLA-4 antibodies [29]. The reported duration from ini‐
tiation of anti-PD-1 antibody treatment to the onset of
type 1 diabetes mellitus ranges from 13 to 504 days [29].
Endocrine Journal Advance Publication
As impaired beta cell function is generally irreversible,
and inappropriate management can directly affect prog‐
nosis, it is important to start insulin therapy as soon as
possible after the early diagnosis of type 1 diabetes mel‐
litus.
Symptoms
The symptoms of type 1 diabetes mellitus induced by
ICIs are thirst, polydipsia and polyuria due to hypergly‐
cemia, general fatigue, and impaired consciousness or
coma due to ketosis or ketoacidosis.
Testing and diagnosis
Laboratory data show increased levels of glucose in
the blood and urine. Although blood glucose levels may
increase to around 1,000 mg/dL, they may be lower in
some cases (e.g. 200–300 mg/dL). The levels of ketone
bodies are increased in blood and urine, indicating keto‐
sis or ketoacidosis. Hemoglobin A1c (HbA1c) levels are
also elevated, although the increase may be relatively
small compared to the raised levels of plasma glucose. C
peptide levels gradually decrease in serum and urine.
Anti-GAD antibodies are generally negative.
Treatment
Insulin therapy must be started for type 1 diabetes
mellitus induced by ICIs. In cases of ketosis or ketoaci‐
dosis, intravenous administration of insulin and saline is
required. After ketosis or ketoacidosis has improved,
intensive insulin therapy (subcutaneous injections) is rec‐
ommended to control glucose levels. Subcutaneous insu‐
lin injections instead of intravenous injections can be
started at the beginning if patients do not develop ketosis
and the increases in blood glucose are small.
It is important to diagnose type 1 diabetes mellitus
before hyperglycemia is accompanied by ketoacidosis.
Therefore, blood glucose levels must be measured at
each visit after treatment with ICIs is started. Attending
physicians (oncologists) should check the glucose levels
on the visit day and consult diabetologists or endocrinol‐
ogists as soon as possible if blood glucose levels are
increased (fasting blood glucose ≧126 mg/dL, casual
blood glucose ≧200 mg/dL). Patients treated with ICIs
should be informed of the possibility that they may
develop type 1 diabetes mellitus following treatment
with ICIs. It is also important for patients to be aware of
the symptoms of hyperglycemia (thirst, polydipsia, and
polyuria), so that they can immediately contact attending
physicians as soon as these symptoms develop.
Glucocorticoids are not recommended for the treat‐
ment of type 1 diabetes mellitus because there is no evi‐
dence to support their use and blood glucose levels
would be increased by glucocorticoids. If patients require
a high dose of glucocorticoids for treatment of other
adverse effects, blood glucose levels should be moni‐
tored carefully.
 Guidelines for endocrine irAEs
The use of ICIs in patients with type 1 diabetes melli‐
tus should be withheld until the general conditions are
stabilized by treatment.
Comments
Endocrine irAEs can lead to life-threatening conse‐
quences such as an adrenal crisis, thyroid storm, severe
hypocalcemia, and diabetic ketoacidosis. Therefore,
endocrinologists and oncologists should understand the
clinical features of endocrine irAEs induced by ICIs.
Because endocrine dysfunction in irAEs is irreversible
in most cases [8], therapy for each endocrine irAE must
be continued. There is no evidence to support the use of
high doses of glucocorticoids for endocrine irAEs,
although severe irAEs in other than endocrine organs are
often treated with high doses of these agents.
In clinical practice, it would be beneficial to identify,
in advance, which patients are at greatest risk of develop‐
ing an endocrine irAEs induced by an ICI. It has been
reported that the presence of TgAb and/or TPOAb in
serum may be potential biomarkers of thyroid dysfunc‐
tion induced by the anti-PD-1 antibody [22, 23]. On the
other hand, there are no reports to date that have shown
predictive biomarkers for endocrine irAEs other than
thyroid dysfunction.
References
1. Postow MA, Sidlow R, Hellmann MD (2018) Immune-
related adverse events associated with immune checkpoint
blockade. N Engl J Med 378: 158–168.
2. Chang LS, Barroso-Sousa R, Tolaney SM, Hodi FS,
Kaiser UB, et al. (2019) Endocrine toxicity of cancer
immunotherapy targeting immune checkpoints. Endocr
Rev 40: 17–65.
3. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB,
Brassil KJ, et al. (2018) Management of immune-related
adverse events in patients treated with immune checkpoint
inhibitor therapy: American Society of Clinical Oncology
Clinical Practice Guideline. J Clin Oncol 36: 1714–1768.
4. Higham CE, Olsson-Brown A, Carroll P, Cooksley T,
Larkin J, et al. (2018) Society for endocrinology endo‐
crine emergency guidance: acute management of the endo‐
crine complications of checkpoint inhibitor therapy.
Endocr Connect 7: G1–G7.
5. The Japan Endocrine Society (2018) A clinical guideline
for the management of immune-related adverse events in
endocrine organs induced by immune checkpoint inhibi‐
tors. Folia Endocrinologica Japonica 94: 1–11. (https://
doi.org/10.1507/endocrine.94.S.November_1) (In Japa‐
nese).
6. Caturegli P, Di Dalmazi G, Lombardi M, Grosso F,
Larman HB, et al. (2016) Hypophysitis secondary to
cytotoxic T-lymphocyte-associated protein 4 blockade:
Endocrine Journal Advance Publication
5
Acknowledgments
The guidelines for diagnosis and treatment of type 1
diabetes mellitus were prepared in collaboration between
the Japan Endocrine Society and the Japan Diabetes
Society.
Author Contributions
All authors discussed these guidelines. S.I. and H.A.
wrote the manuscript. All authors assisted with revision
of the manuscript.
Disclosure Summary
H.A. received a speaker fee from MSD. K.K., research
funding from Ono Pharmaceutical Company, and schol‐
arship donations from MSD K.K., Pfizer Inc. and Ono
Pharmaceutical Company. A.I. received a speaker fee
from Ono Pharmaceutical Company and research fund‐
ing from Bristol-Myers Squibb and Chugai Pharmaceuti‐
cal Company. The remaining authors have nothing to
disclose.
insights into pathogenesis from an autopsy series. Am J
Pathol 186: 3225–3235.
7. Bertrand A, Kostine M, Barnetche T, Truchetet ME,
Schaeverbeke T (2015) Immune related adverse events
associated with anti-CTLA-4 antibodies: systematic
review and meta-analysis. BMC Med 13: 211.
8. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M (2017)
Cancer immunotherapy—immune checkpoint blockade
and associated endocrinopathies. Nat Rev Endocrinol 13:
195–207.
9. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi
FS, Min L, et al. (2017) Incidence of endocrine dysfunc‐
tion following the use of different immune checkpoint
inhibitor regimens: a systematic review and meta-analysis.
JAMA Oncol 4: 173–182.
10. Gonzalez-Rodriguez E, Rodriguez-Abreu D, Spanish
Group for Cancer Immuno-Biotherapy (GETICA) (2016)
Immune checkpoint inhibitors: review and management of
endocrine adverse events. Oncologist 21: 804–816.
11. Cukier P, Santini FC, Scaranti M, Hoff AO (2017) Endo‐
crine side effects of cancer immunotherapy. Endocr Relat
Cancer 24: T331–T347.
12. Okano Y, Satoh T, Horiguchi K, Toyoda M, Osaki A, et
al. (2016) Nivolumab-induced hypophysitis in a patient
with advanced malignant melanoma. Endocr J 63: 905–
912.
6 Arima et al.
13. Cho KY, Miyoshi H, Nakamura A, Kurita T, Atsumi T
(2017) Hyponatremia can be a powerful predictor of the
development of isolated ACTH deficiency associated with
nivolumab treatment [Letter to the Editor]. Endocr J 64:
235–236.
14. Kanie K, Iguchi G, Bando H, Fujita Y, Odake Y, et al.
(2018) Two cases of atezolizumab-induced hypophysitis. J
Endocr Soc 2: 91–95.
15. Ohara N, Ohashi K, Fujisaki T, Oda C, Ikeda Y, et al.
(2018) Isolated adrenocorticotropin deficiency due to
nivolumab-induced hypophysitis in a patient with
advanced lung adenocarcinoma: a case report and litera‐
ture review. Intern Med 57: 527–535.
16. Min L, Hodi FS, Giobbie-Hurder A, Ott PA, Luke JJ, et al.
(2015) Systemic high-dose corticosteroid treatment does
not improve the outcome of ipilimumab-related hypophy‐
sitis: a retrospective cohort study. Clin Cancer Res 21:
749–755.
17. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R,
et al. (2018) High-dose glucocorticoids for the treatment
of ipilimumab-induced hypophysitis is associated with
reduced survival in patients with melanoma. Cancer 124:
3706–3714.
18. Yanase T, Tajima T, Katabami T, Iwasaki Y, Tanahashi Y,
et al. (2016) Diagnosis and treatment of adrenal insuffi‐
ciency including adrenal crisis: a Japan Endocrine Society
clinical practice guideline [Opinion]. Endocr J 63: 765–
784.
19. Trainer H, Hulse P, Higham CE, Trainer P, Lorigan P
(2016) Hyponatraemia secondary to nivolumab-induced
primary adrenal failure. Endocrinol Diabetes Metab Case
Rep 2016.
20. Min L, Ibrahim N (2013) Ipilimumab-induced autoim‐
mune adrenalitis. Lancet Diabetes Endocrinol 1: e15.
21. Inaba H, Ariyasu H, Okuhira H, Yamamoto Y, Akamatsu
H, et al. (2018) Endocrine dysfunctions during treatment
Endocrine Journal Advance Publication
of immune-checkpoint inhibitors. Trends Immunother 2:
565.
22. Kobayashi T, Iwama S, Yasuda Y, Okada N, Tsunekawa
T, et al. (2018) Patients with antithyroid antibodies are
prone to develop destructive thyroiditis by nivolumab: a
prospective study. J Endocr Soc 2: 241–251.
23. Kimbara S, Fujiwara Y, Iwama S, Ohashi K, Kuchiba A,
et al. (2018) Association of antithyroglobulin antibodies
with the development of thyroid dysfunction induced by
nivolumab. Cancer Sci 109: 3583–3590.
24. Win MA, Thein KZ, Qdaisat A, Yeung SJ (2017) Acute
symptomatic hypocalcemia from immune checkpoint
therapy-induced hypoparathyroidism. Am J Emerg Med
35: 1039 e1035–1039 e1037.
25. Umeguchi H, Takenoshita H, Inoue H, Kurihara Y,
Sakaguchi C, et al. (2018) Autoimmune-related primary
hypoparathyroidism possibly induced by the administra‐
tion of pembrolizumab: a case report. J Oncol Pract 14:
449–451.
26. Trinh B, Sanchez GO, Herzig P, Laubli H (2019)
Inflammation-induced hypoparathyroidism triggered by
combination immune checkpoint blockade for melanoma.
J Immunother Cancer 7: 52.
27. Piranavan P, Li Y, Brown E, Kemp EH, Trivedi N (2019)
Immune checkpoint inhibitor-induced hypoparathyroidism
associated with calcium-sensing receptor-activating auto‐
antibodies. J Clin Endocrinol Metab 104: 550–556.
28. The Japan Diabetes Society (2016) A recommendation for
type 1 deiabetes mellitus in patients treated with immune
checkpoint inhibitors (http://www.jds.or.jp/modules/
important/index.php?page=article&storyid=58) (In Japa‐
nese).
29. Baden MY, Imagawa A, Abiru N, Awata T, Ikegami H, et
al. (2019) Characteristics and clinical course of type 1 dia‐
betes mellitus related to anti-programmed cell death-1
therapy. Diabetol Int 10: 58–66.