Introduction: In the last few years, immune checkpoint inhibitors (ICPis) have become a common treatment of cancer. ICPis are associated with peculiar immune side effects, termed immune-related adverse events (irAEs). Thyroid disfunction is a common irAE, but clinical manifestation, severity, and pathogenesis can be variable. While destructive thyroiditis and hypothyroidism are the most common thyroid irAEs induced by ICPis, autoimmune hyperthyroidism (Graves’ disease) is rare. We describe a case of a Graves’ disease induced by anti-PD-1 therapy and we review the previous reports on this issue. Case Presentation: A 51-year-old man developed an overt autoimmune hyperthyroidism 2 months after he had started nivolumab (anti-PD-1) therapy for a metastatic non-small cell lung cancer. Although TSH-receptor autoantibodies (TRAb) were negative, the persistence of hyperthyroidism, the hypervascular pattern at thyroid ultrasound, and the high uptake at thyroid scintigraphy were all features suggestive of Graves’ disease. Methimazole was started with the prompt restoration of euthyroidism. TRAb remained undetectable during the entire follow-up. Conclusions: Autoimmune hyperthyroidism can be induced by anti-PD-1 treatment. TRAb were negative in both cases of nivolumab-induced Graves’ disease described to date. A correct differential diagnosis between destructive thyroiditis and autoimmune hyperthyroidism is crucial for the appropriate treatment.

1.
Chang
LS
,
Barroso-Sousa
R
,
Tolaney
SM
,
Hodi
FS
,
Kaiser
UB
,
Min
L
.
Endocrine toxicity of cancer immunotherapy targeting immune checkpoints
.
Endocr Rev
.
2019
Feb
;
40
(
1
):
17
65
.
[PubMed]
1945-7189
2.
Delivanis
DA
,
Gustafson
MP
,
Bornschlegl
S
,
Merten
MM
,
Kottschade
L
,
Withers
S
, et al.
Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms
.
J Clin Endocrinol Metab
.
2017
Aug
;
102
(
8
):
2770
80
.
[PubMed]
0021-972X
3.
Menconi
F
,
Marcocci
C
,
Marinò
M
.
Diagnosis and classification of Graves’ disease
.
Autoimmun Rev
.
2014
Apr-May
;
13
(
4-5
):
398
402
.
[PubMed]
1568-9972
4.
Minelli
R
,
Spagnoli
F
,
Marchesi
E
,
Venturi
N
,
Marina
M
,
Orlandini
A
, et al.
Course of graves disease in interferon-treated patients with chronic hepatitis C virus infection and in uninfected patients
.
J Investig Med
.
2013
Dec
;
61
(
8
):
1173
7
.
[PubMed]
1081-5589
5.
Heath
G
,
Airody
A
,
Peter
R
,
Gale
RP
.
The Ocular Manifestations of Drugs Used to Treat Multiple Sclerosis. Drugs
[
Internet
]
Springer International Publishing
;
2017
.
6.
Osorio
JC
,
Ni
A
,
Chaft
JE
,
Pollina
R
,
Kasler
MK
,
Stephens
D
, et al.
Antibody-Mediated Thyroid Dysfunction During T-cell Checkpoint Blockade in Patients with Non-Small Cell Lung Cancer. Ann Oncol.
2017
; 1;28(3):583-589.
7.
Tozzoli
R
,
Bagnasco
M
,
Giavarina
D
,
Bizzaro
N
.
TSH receptor autoantibody immunoassay in patients with Graves’ disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis
.
Autoimmun Rev
.
2012
Dec
;
12
(
2
):
107
13
.
[PubMed]
1568-9972
8.
Borodic
G
,
Hinkle
DM
,
Cia
Y
.
Drug-induced graves disease from CTLA-4 receptor suppression
.
Ophthal Plast Reconstr Surg
.
2011
Jul-Aug
;
27
(
4
):
e87
8
.
[PubMed]
0740-9303
9.
Min
L
,
Vaidya
A
,
Becker
C
.
Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy
.
Eur J Endocrinol
.
2011
Feb
;
164
(
2
):
303
7
.
[PubMed]
0804-4643
10.
McElnea
E
,
Ní Mhéalóid
A
,
Moran
S
,
Kelly
R
,
Fulcher
T
.
Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab
.
Orbit
.
2014
Dec
;
33
(
6
):
424
7
.
[PubMed]
0167-6830
11.
Azmat
U
,
Liebner
D
,
Joehlin-price
A
,
Agrawal
A
,
Nabhan
F
,
Report
C.
Case Report Treatment of Ipilimumab Induced Graves ’ Disease in a Patient with Metastatic Melanoma.
2016
;2016(Table 1):1–5.
12.
Gan
EH
,
Mitchell
AL
,
Plummer
R
,
Pearce
S
,
Perros
P
.
Tremelimumab-Induced Graves Hyperthyroidism.
2017
;167–70.
13.
Park
ES
,
Rabinowits
G
,
Hamnvik
OR
,
Dagi
LR
.
A case of Graves’ ophthalmopathy associated with pembrolizumab (Keytruda) therapy
.
J AAPOS
.
2018
Aug
;
22
(
4
):
310
2
.
[PubMed]
1091-8531
14.
Campredon
P
,
Imbert
P
,
Mouly
C
,
Grunenwald
S
,
Mazières
J
,
Caron
P
.
Severe Inflammatory Ophthalmopathy in a Euthyroid Patient during Nivolumab Treatment
.
Eur Thyroid J
.
2018
Mar
;
7
(
2
):
84
7
.
[PubMed]
2235-0640
15.
Iadarola
C
,
Croce
L
,
Quaquarini
E
,
Teragni
C
,
Pinto
S
,
Bernardo
A
, et al.
Nivolumab Induced Thyroid Dysfunction : Unusual Clinical Presentation and Challenging Diagnosis. Front Endocrinol (Lausanne).
2019
; 17;9:813.
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