The incidence of thyrotoxicosis induced by ICIs is 10% to 20% in patients treated with anti–CTLA-4 (10%-20%) and, 30% to 40% in those treated with PD1 or PD-L1 blockade.[3,8,9] The different role of the CTLA-4 and PD1/PD-L1 pathways in immune regulation accounts for this difference; CTLA-4 plays a key role in central tolerance, whereas the PD1/PD-L1 pathway modulates the immune response in peripheral tissue.[10,11] The term "thyrotoxicosis" reported in clinical trials includes several scenarios ranging from destructive thyroiditis to primary hyperthyroidism, which differ in their physiopathology, course, and treatment. The lack of a full endocrinological evaluation hampers the characterization of patients included in clinical trials of ICIs published to date. For this reason, we have decided to investigate a cohort of patients who experienced thyrotoxicosis induced by anti-PD1 or anti–PD-L1 drugs.
Current guidelines and expert opinion on the management of irAEs recommend neck ultrasound and thyroid scintigraphy only in selected cases.[3,12] The usefulness of thyroid scintigraphy is questioned because of the potential interference of the iodine contrast agent used for CT scans. The washout time of iodine contrast media is reported to range from 15 days to 6 to 12 months.[13–15] Instead, 3.5 months after the last CT scan, we found levels of urine iodine only slightly higher compared to the Italian population, but not high enough to influence the result of thyroid scintigraphy, as confirmed by our finding of similar levels in the 2 groups of patients (Sci– and Sci+). Scintigraphy with iodine isotopes that are organified by the thyroid (131I or 123I) may have provided a better characterization of our cohorts of patients. Specifically, 99mTc-pertechnetate is more available and less expensive than iodine isotopes, and 99mTc-scintiscan is carried out faster than iodine scintigraphy (20 minutes vs 24 hours), which is a favorable feature in oncological patients.[15,17] Although measurement of technetium uptake might add useful data, the presence (Sci+) or absence (Sci–) of a thyroid image via 99mTc-scintiscan were sufficient to identify those patients who were responsive to methimazole treatment in our cohort.
A high rate of participants, mainly in the Sci– cohort, had the de novo appearance of TgAbs or, less frequently, of TPOAbs, likely as consequence of the humoral response to the release of antigens secondary to thyroid destruction.[18,19]
The rate of persistent hyperthyroidism was higher in our cohort compared to that previously reported. This discrepancy might be due to the inclusion of patients with severe forms of thyrotoxicosis. All 5 Sci+ patients had no feature of thyroid autoimmunity before the start of ICIs, and only 1 showed positive TPOAbs and TgAbs at the onset of thyrotoxicosis. Moreover, in none of the 5 Sci+ patients did we observe the appearance of TRAbs (measured by a sensitive assay), a finding that would have enabled us to identify Graves disease.[20,21] These findings are similar to those reported in most cases of persistent hyperthyroidism induced by anti-PD1 or anti–PD-L1 agents so far reported. Interestingly enough, we did not observe a rise in Tg levels, which is typical of destructive thyrotoxicosis (131I treatment or subacute thyroiditis) as well as of autoimmune hyperthyroidism. The coexistence in some patients of serum TgAbs, which interfere with the detection of Tg, is the most likely reason for this finding.[6,23] However, 6 patients in our cohort had low Tg levels in spite of undetectable TgAbs. This finding raises the possibility that these patients had serum M class TgAbs, which are not detected by commercial assays.
As previous studies reported that most cases of thyrotoxicosis induced by anti-PD1 or anti–PD-L1 agents are self-limited and transient, treatment with MMI was inappropriately delayed in some Sci+ patients. On the other hand, given the absence of a standardized treatment of thyrotoxicosis induced by PD1 and PD-L1 blockade, some patients with more severe thyrotoxicosis were treated with MMI despite an absent uptake at scintigraphy. These misjudgments enabled us to identify scintigraphy as a useful tool to select those patients who would benefit from treatment with MMI.
Patients with destructive thyrotoxicosis developed hypothyroidism in agreement with several studies reporting a rate of hypothyroidism after destructive thyroiditis of 60% to 80%.[3,8,18] For the first time, we show that the risk of developing hypothyroidism is inversely related to thyroid volume, individuals with normal volume being at higher risk compared to those with goiter. Noteworthy, should overt hypothyroidism abruptly ensue after thyrotoxicosis, we advise a close monitoring of thyroid function after remission of thyrotoxicosis in order to promptly identify and treat hypothyroidism.
The relevance of ultrasound and scintigraphy performed at the onset of thyrotoxicosis in allowing the proper diagnosis, in the prediction of the course of the disease, as well as choosing the appropriate treatment are the main findings of this study. Based on these findings, we identified 2 different types of thyrotoxicosis induced by immunotherapy. Similarly to amiodarone-induced thyrotoxicosis (AIT), we identified a type 1 characterized by persistent hyperthyroidism that responds to antithyroid drugs, and a type 2, characterized by destructive thyroiditis that evolves into euthyroidism or hypothyroidism. Measurement of Tg and calculation of the FT3/FT4 ratio might be useful to differentiate these 2 forms. However, our data showed that both Tg and FT3/FT4 were not reliable in differentiating the 2 types of thyrotoxicosis; neither were they helpful in distinguishing AIT type 1 from AIT type 2. Since treatment with anti-PD1 and anti–PD-L1 drugs has been reported to be associated with a change in the levels of cytokines, it would be interesting to evaluate in future studies whether the onset and the phenotype of thyrotoxicosis is associated with a specific change in cytokine pattern.
In conclusion, patients treated with anti-PD1 or anti–PD-L1 drugs may undergo 2 types of thyrotoxicosis that do not differ in severity at their onset. Thyroid scintigraphy and ultrasound are useful, low-invasive, and low-cost benefit tools in the management of thyrotoxicosis induced by PD1 and PD-L1 blockade.
The authors wish to thank Maria Di Blasi and the nursing staff for their help in the management of the patients included in the study. We would like to thank Mrs Stephanie Marino for editing this manuscript.
This work was supported by "Fondi di Ateneo," the University of Pisa No. 539901/2020 to FL and "Contributo Shire International GmbH" to CM.
J Endo Soc. 2021;5(9) © 2021 Endocrine Society