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


J Endo Soc. 2021;5(9) 

In This Article


Thyroid Features at Baseline and at Onset of Thyrotoxicosis

Thyroid features at baseline and at the onset of thyrotoxicosis of each patient are reported in Table 1 and summarized in Table 2. At baseline, all patients were euthyroid with negative TgAbs and TPOAbs. Thyroid volume at neck ultrasound was 22.4 mL (range, 10.8–29.9 mL) (median and interquartile range). Thyroid volume was normal in 9 patients, whereas 11 individuals had goiter. The echoic pattern was normal in 6 patients, slightly hypoechoic in 9, and frankly hypoechoic in 5. Thyroid nodules were detected in 5 patients; in 2 of them we performed fine-needle biopsy, which turned out benign. At 99mTc-scintiscan, 5 patients were classified as Sci+ and 15 as Sci–. Sci+ patients showed a larger thyroid volume compared to Sci– (27.9 vs 12.0 mL; P = .03). Evaluating only patients with TgAbs less than 9.3 IU/mL (the interfering cutoff of the assay), the Tg levels were similar in Sci+ (N = 4) and in Sci– (N = 7) patients (12.4 in Sci+ vs 6.7 in Sci–, P = .38). The FT3/FT4 ratio was similar in the 2 groups (0.26 in Sci+ vs 0.28 in Sci–, P = .79).

Factors Influencing the Severity and Time Course of Thyrotoxicosis in Untreated Patients

At baseline, FT4 and FT3 levels did not differ when comparing patients with goiter with those with normal thyroid volume. Additionally, FT4 and FT3 were similar in Sci+ and Sci– patients. The course of thyrotoxicosis was ascertained evaluating the levels of FT4 and FT3 during follow-up. Patients were excluded from the analysis once they started thyroid treatment (antithyroid drugs or levothyroxine). FT4 and FT3 were higher in patients with goiter compared to those with normal thyroid volume at days 28, 42, 56, 70, and 84 (P < .05 for all) (Figure 2A and 2B). FT4 and FT3 were higher in Sci+ patients compared to Sci– patients at days 28, 42, 56 or 63, 70, and 84 (P < .05 for all) (Figure 2C and 2D). Analysis was stopped at day 84 because only 4 patients were left untreated afterward.

Figure 2.

Changes in free thyroxine (FT4) and free 3,5,3'-triiodothyronine (FT3) concentrations according to A and B, thyroid volume, and C and D, uptake of technetium in patients with thyrotoxicosis induced by PD-1 or PD-L1 blockade. Time 0 indicates the onset of thyrotoxicosis. Patients were excluded when they started thyroid treatment (methimazole or levothyroxine). The number of patients at each time point in both groups is reported. Gray areas indicate normal values of FT4 and FT3. *P less than .05 between the 2 groups.

Efficacy of Treatment With Methimazole

Five Sci+ and 6 Sci– patients started treatment with methimazole (MMI) at different times during follow-up. The 2 groups were treated with a comparable dosage of antithyroid drug (140 mg/week in Sci+ vs 145 mg/week in Sci–). The decrease in FT4 and FT3 levels was greater in Sci+ compared to Sci– patients at days 14 and 28 (P < .001 for both) (Figure 3A and 3B). Whereas all 6 Sci– patients discontinued MMI after a median period of 40 days because it was ineffective on thyrotoxicosis, all 5 Sci+ patients were still treated with MMI at the end of follow-up at the median dosage of 35 mg/week. Their median levels of FT4 (13.8 ng/L), FT3 (4.3 ng/L), and TSH (2.9 mIU/mL) were all in the normal range.

Figure 3.

Changes in A, free thyroxine (FT4) and B, free 3,5,3'-triiodothyronine (FT3) concentrations after the start of methimazole therapy in 5 patients with normal/increased uptake of technetium (Sci+) and in 6 with absent uptake (Sci–). Gray areas indicate normal values of FT4 and FT3.*P less than .05 between the 2 groups.

Thyrotoxicosis Remission

Remission of thyrotoxicosis was observed in all 15 Sci– patients: 9 never treated and 6 previously treated with MMI. Time to remission was 45 ± 15 days (mean ± SD) in the entire Sci– group and 70 ± 15 days in the cohort of the 6 Sci– patients previously treated with MMI. At univariate analysis, time to remission was associated with a larger thyroid volume and higher levels of FT4 and TgAbs at the onset of thyrotoxicosis. At multivariate analysis, only a larger thyroid volume was associated with a longer time to remission.

Onset of Hypothyroidism

Of the 15 Sci– patients, 9 experienced hypothyroidism; none of them belonged to the cohort of patients treated with MMI. Hypothyroidism developed within days 14 to 84 (Figure 4A and 4B) and was more common in patients with normal thyroid volume than in those with goiter (7/9 vs 2/11; P = .04). All patients started replacement treatment and showed normal thyroid tests at the end of follow-up while taking 75 μg/day of levothyroxine (median dosage).

Figure 4.

Trend of A, free thyroxine (FT4) and B, thyrotropin (TSH) in the 15 individuals with absent uptake of technetium (Sci–). Patients are listed according to increasing thyroid volume. Gray areas indicate normal values of FT4 and TSH. The dashed line in A indicates the time when the patients were on methimazole treatment.