Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade

Alessandro Brancatella; Isabella Lupi; Lucia Montanelli; Debora Ricci; Nicola Viola; Daniele Sgrò; Lucia Antonangeli; Chiara Sardella; Sandra Brogioni; Paolo Piaggi; Eleonora Molinaro; Francesca Bianchi; Michele Aragona; Andrea Antonuzzo; Andrea Sbrana; Maurizio Lucchesi; Antonio Chella; Alfredo Falcone; Stefano del Prato; Rossella Elisei; Claudio Marcocci; Patrizio Caturegli; Ferruccio Santini; Francesco Latrofa

Disclosures

J Endo Soc. 2021;5(9)

Abstract and Introduction

Abstract

Context: Thyrotoxicosis is a common immune-related adverse event in patients treated with programmed cell death protein-1 (PD1) or programmed cell death protein ligand-1 (PD-L1) blockade. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy, is lacking, as are data on response to treatment and follow-up.

Objective: The aim of this study was to better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and treatment.

Methods: We conducted a retrospective study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis on PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, ^99mtechnecium scintiscan, and longitudinal thyroid function tests.

Results: Five patients had normal or increased scintigraphic uptake (Sci+), no serum antibodies against the thyrotropin receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci–) and experienced destructive thyrotoxicosis followed by hypothyroidism (N = 9) or euthyroidism (N = 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P = .04). Among Sci– individuals, a larger thyroid volume was associated with a longer time to remission (P < .05). Methimazole (MMI) was effective only in Sci+ individuals (P < .05).

Conclusion: Administration of PD1- or PD-L1–blocking antibodies may induce 2 different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2, characterized by destructive and transient thyrotoxicosis that evolves to hypothyroidism or euthyroidism. Thyroid scintigraphy and ultrasound help in differentiating and managing these 2 forms of iatrogenic thyrotoxicosis.

Introduction

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies directed toward receptors expressed on T cells and other cell types of peripheral tissue, namely cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein-1 (PD1), and programmed cell death protein ligand-1 (PD-L1). By blocking these molecules, ICIs promote the activation of the immune system against cancer and as such are effective in the treatment of many solid tumors.^[1,2] The hyperactivation of the immune system induced by ICIs can also generate a broad spectrum of inflammatory tissue reaction acknowledged as immune-related adverse events (irAEs).^[2] Thyroid dysfunction and hypophysitis are the most common endocrine irAEs, followed by type 1 diabetes and adrenalitis, whereas autoimmune hypoparathyroidism and central diabetes insipidus have been less frequently reported.^[3–5] Thyroid dysfunction can be a consequence of PD1 and PD-L1 blockade; however, it has not been fully characterized because trials have focused for the most part on the epidemiology of irAEs rather than on their clinical presentation and course.

An exhaustive endocrinological investigation, including a systematic analysis of thyroid ultrasound and scintigraphy, as well as data on the response to treatment and follow-up, are lacking.

The aim of the present study was to characterize ICI-induced thyrotoxicosis by hormonal and antibodies assessment and thyroid ultrasound and scintigraphic imaging in order to gain insights into its pathogenesis and to guide its management.

1 2 3 4

Next Section

Abstract and Introduction
Material and Methods
Results
Discussion
References

Table 1. Thyroid features of the 20 patients at the onset of thyrotoxicosis induced by immunotherapy
Patient	Sex, M/F	Age, y	Cancer	Drug	Time from ICI start, mo	FT4, ng/L	FT3, ng/L	TgAbs, IU/mL	TPOAbs, IU/mL	TRAbs, IU/mL	Tg, ng/mL	Urinary iodine, μg/L	Thyroid volume, mL	^99mTc-uptake, Sci+/Sci–
1	F	69	NSCLC	Pembro	1	30.5	10.7	69	125	< 0.1	0.91	219	4.6	Sci–
2	F	46	NSCLC	Nivo	3	19.7	4.3	13	< 1.0	< 0.1	4.96	190	6.1	Sci–
3	M	73	HCC	Pembro	2	28.5	6.7	< 1.0	24	< 0.1	3.7	180	6.5	Sci–
4	M	53	NSCLC	Atezo	2	29.8	9.1	180	< 1.0	< 0.1	4.9	286	7.0	Sci–
5	F	41	MEL	Nivo	4	21.1	5.9	< 1.0	< 1.0	< 0.1	2.2	290	9.0	Sci–
6	F	49	MEL	Nivo	5	29.9	11.0	20	< 1.0	< 0.1	11.0	190	11.4	Sci–
7	M	71	NSCLC	Pembro	6	33.0	8.8	< 1.0	< 1.0	< 0.1	2.7	190	12.0	Sci–
8	M	77	MEL	Nivo	1	17.6	3.4	12	< 1.0	< 0.1	0.72	200	12.1	Sci–
9	M	62	RCC	Nivo	2	39.5	12.2	262	967	< 0.1	6.97	252	22.0	Sci–
10	M	71	NSCLC	Nivo	2	19.1	3.9	< 1.0	< 1.0	< 0.1	2.98	221	22.8	Sci–
11	F	71	NSCLC	Pembro	2	37.1	5.2	178	< 1.0	0.12	79.7	276	23.7	Sci–
12	M	70	MEL	Nivo	9	30.9	8.8	< 1.0	< 1.0	< 0.1	9.2	280	25.3	Sci–
13	M	65	MEL	Nivo	1	31.1	8.7	400	199	< 0.1	1.3	190	36.2	Sci–
14	M	67	NSCLC	Pembro	2	35.5	5.7	< 1.0	< 1.0	< 0.1	81.0	200	37.0	Sci–
15	M	74	HCC	Durva	1	43.8	7.3	2000	< 1.0	0.1	1.8	283	38.7	Sci–
16	M	51	NSCLC	Nivo	2	29.3	11.2	< 1.0	< 1.0	< 0.1^a	21.0	190	16.4	Sci+
17	F	55	NSCLC	Nivo	1	26.6	5.6	< 1.0	< 1.0	< 0.1^a	18.8	220	25.3	Sci+
18	F	55	NSCLC	Pembro	2	30.7	7.2	1000	70	< 0.1^a	2.7	290	27.9	Sci+
19	M	51	MEL	Pembro	1	20.2	4.4	< 1.0	< 1.0	< 0.1^a	3.8	298	42.0	Sci+
20	M	71	NSCLC	Atezo	2	29.7	7.7	< 1.0	< 1.0	< 0.1^a	79.1	216	48.0	Sci+

Normal ranges: FT4 8 to 18 ng/L; FT3 2.5 to 5.0 pmol/L; TgAbs less than 30 IU/mL; TPOAbs less than 10 IU/mL; TRAbs less than 1.5 IU/mL; Tg less than 30 μg/L; urinary iodine 100 to 300 μg/L; normal thyroid volume: 12.1 mL (female); 16.5 mL (male).
Sci+ indicates patients with formation of a thyroid image due to a normal/increased uptake of technetium; Sci– indicates patients without formation of a thyroid image due to an absent uptake.
Abbreviations: Atezo, atezolizumab (anti-PD-L1); Durva, durvalumab (anti-PD-L1); F, female; FT3, free 3,5,3'-triiodothyronine; FT4, free thyroxine; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; M, male; MEL, melanoma; Nivo, nivolumab; NSCLC, non–small cell lung cancer; Pembro, pembrolizumab (anti-PD1); PD1, programmed cell death protein-1; PD-L1, programmed cell death protein ligand-1; RCC, renal cell carcinoma; Tc, technecium; Tg, thyroglobulin; TgAbs, thyroglobulin antibodies; TPOAbs, thyroperoxidase antibodies; TRAbs, thyrotropin receptor antibodies.
^aTRAb were negative at 3 different times during the follow-up.

Table 2. Thyroid features at baseline and at the onset of thyrotoxicosis
Laboratory testing (normal range)	Baseline	Day 0
FT4 (8–18 ng/L)	12.7 (10.9–14.5) ng/L	29.8 (25.2–30.5) ng/L
FT3 (2.5–5 ng/L)	3.9 (3.6–4.3) ng/L	7.3 (5.5–8.9) ng/L
FT3/FT4 ratio	0.31 (0.28–0.34)	0.25 (0.29–0.32)
TSH (0.4–4 mIU/L)	1.5 (0.9–2.4) mIU/mL	0 (0-0) mIU/L
TgAbs (< 30 IU/mL)
Positive	0	7
Level		179 (32.2–365.5) IU/mL
TPOAbs (< 10 IU/mL)
Positive	0	5
Level		125 (70–199) IU/mL
TRAbs (< 1.5 IU/mL)
Positive		0
Urinary iodine (100–300 μg/L)		219.5 (190–287) μg/L
Thyroglobulin (< 30 ng/mL)		4.4 (2.3–10.5) ng/mL
Imaging
Ultrasound
Thyroid volume (6–16 mL)		22.8 (10.8–29.9) mL
Echoic pattern
Normoechoic		6
Slightly hypoechoic		9
Frankly hypoechoic		5
Patients with nodules		5
^99mTc-scintigraphy
Sci+		5
Sci–		15

Laboratory tests with normal values, thyroid volume with normal value, different echoic pattern, nodules, and diverse scintigraphy pattern are reported.
Baseline: screening performed before the start of immunotherapy. FT4, FT3, FT3/FT4 ratio, TSH, and TgAbs are reported as median (25th-75th percentile). Number of patients with positive TgAbs and TPOAbs are also reported.
Day 0: time of onset of thyrotoxicosis.
FT4, FT3, FT3/FT4 ratio, TSH, TgAbs, TPOAbs, TRAbs, urinary iodine, thyroglobulin, and thyroid volume are reported as median (25th-75th percentile).
Number of patients with positive TgAbs, TPOAbs, and TRAbs, echoic pattern, nodules, and distinct scintigraphy pattern are reported.
Abbreviations: FT3, 3,5,3'-free triiodothyronine; FT4, free thyroxine; Tc, technetium; Tg, thyroglobulin; TgAbs, thyroglobulin antibodies; TPOAbs, thyroperoxidase antibodies; TRAbs, thyrotrophin receptor antibodies; TSH, thyrotrophin.

Authors and Disclosures

Alessandro Brancatella¹, Isabella Lupi², Lucia Montanelli², Debora Ricci¹, Nicola Viola¹, Daniele Sgrò¹, Lucia Antonangeli², Chiara Sardella², Sandra Brogioni², Paolo Piaggi³, Eleonora Molinaro², Francesca Bianchi⁴, Michele Aragona⁵, Andrea Antonuzzo⁶, Andrea Sbrana⁷, Maurizio Lucchesi⁸, Antonio Chella⁸, Alfredo Falcone⁹, Stefano del Prato¹⁰, Rossella Elisei¹¹, Claudio Marcocci¹¹, Patrizio Caturegli¹², Ferruccio Santini¹¹ and Francesco Latrofa¹¹

¹Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy; ²Endocrinology Unit, Azienda Ospedaliero-Universitaria Pisana, University Hospital of Pisa, Pisa 56124, Italy; ³Department of Information Engineering, University of Pisa, Pisa 56126, Italy; ⁴Nuclear Medicine Unit, Azienda Ospedaliero-Unuversitaria Pisana, University Hospital of Pisa, Pisa 56124, Italy; ⁵Metabolic Diseases and Diabetes Unit, Azienda Ospedaliero-Universitaria Pisana, University Hospital of Pisa, Pisa 56124, Italy; ⁶Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, University Hospital of Pisa, Pisa 56126, Italy ⁷Oncology Unit, Azienda Ospedaliero-Universitaria Pisana and Department of Translational Research and New Technologies in Medicine and Surgery, University Hospital of Pisa, Pisa 56126, Italy ⁸Pneumology Unit, Azienda Ospedaliero-Universitaria Pisana, University Hospital of Pisa, Pisa 56124, Italy; ⁹Oncology Unit, Azienda Ospedaliero-Univeritaria Pisana and Department of Translational Research and New Technologies in Medicine abd Surgery, University Hospital of Pisa, Pisa 56126, Italy; ¹⁰Metabolic Diseases and Diabetes Unit, Azienda Ospedaliero-Universitaria Pisana and Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56124, Italy; ¹¹Endocrinology Unit, Azienda Ospedaliero-Universitaria Pisana and Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56124, Italy; and ¹²Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

Correspondence
Francesco Latrofa, MD, Endocrinology Unit I, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, Pisa 56124, Italy. Email: francesco.latrofa@unipi.it.

Disclosures
The authors have nothing to disclose.

Author Contributions
A.B., I.L., and F.L. planned the study. A.B., I.L., L.M., F.S., P.C., and F.L. wrote the manuscript. P.P. performed the statistical analysis. All authors discussed the results of the study.