Table 3 Cases of immune checkpoint inhibitors-induced thyrotoxicosis and hypothyroidism

Reports

7 (2 on same case)

31

16

21

Cases

6

67

29

50

Gender

Males = 4; Females = 2

Males = 27; Females = 27;

Not reported =13

Males = 12; Females = 11; Not reported = 6

Males = 23; Females = 18; Not reported =9

Age (years)

Median = 54.5;

Mean + SD = 57.3 + 7.3

Range = 51–67

Median = 61

Mean + SD = 62.1 + 12.8

Range = 24–88

Median = 64

Mean + SD = 64.1 + 7.9

Range = 46–85

Median = 63

Mean + SD = 64.1 + 10.4

Range = 42–86

Pertinent medical history

PHx + FHx of ThyD

Reported = 2;

Not reported = 4

PHx + FHx of AutoD

Not reported = 6

PHx ThyD: Reported 4;

Not reported 63.

FHx ThyD: Reported 3.

Not reported 64.

HxAutoD: Reported 2;

Not reported 65

PHx ThyD: Reported 5;

Not Reported 24

FHx ThyD: Reported 0;

Not reported 29

HxAutoD: Reported 1;

Not reported 28

PHx ThyD: Reported 13;

Not reported 37.

FHx ThyD. Reported 2;

Not reported 48.

Hx AutoD: Reported = 1;

Not reported 49.

Type of cancer

Melanoma = 6

Melanoma = 39, NSCLC =9; Breast Ca =1; Lung Ca = 5; RCC = 4; Multiple myeloma = 1; Esophageal Ca = 1; Not reported = 7

Melanoma = 18; Jaw Sq Ca = 1; Lung Sq Ca =6; RCC = 2; Bladder Ca = 1; Multiple myeloma = 1.

Melanoma = 29; NSCLC = 8; RCC = 4; Multiple myeloma = 1; breast CA = 1; Lung Ca = 3; Not reported =3.

Check point inhibitor(s)

Ipi = 4; Nivo + Ipi = 1,

Tremeli = 1.

Ipi + bevacizumab = 2; Nivo = 23; Pembro =14; Anti-PD-1 = 6; Ipili = 6; Nivo + Ipili = 7; Ipili+Pembro =1; Ipili, then Pembro = 8.

Ipi = 2; PDL-1 = 1; Nivo = 15; Ipi, then Pembro = 9; Nivo+Ipi =2.

Nivo = 17; Pembro = 13; Anti-PD-1 = 6; Ipili = 2; Nivo+Ipili = 7; Ipili then, Pembro = 5.

ICI Drug D/C?

Yes = 3; Not reported =3

Yes = 12; No = 15; Not reported = 40

Yes =8; No = 5; Not reported = 16

Yes = 8; No = 14; Not reported = 28

Clinical presentation

2 with Graves’ Eye disease (GED)

4 with thyrotoxicosis

Hyperthyroidism symptoms = 43; Asymptomatic = 11;

Not reported =13

Hypothyroid symptoms = 14; Asymptomatic = 3; Not reported =12. DKA = 2; cardiac = 2; adrenal insufficiency = 2

Many cases do not describe symptoms of hypothyroidism in contrast to symptoms of hyperthyroidism.

Onset after first dose (weeks)

Median = 7

Mean + SD = 75.8 + 166.8 Range 6–416

Median = 6

Mean + SD = 7.2 + 5.6

Range 3–28

Median = 12

Mena + SD = 14.2 + 7.1

Range 7–36

Median = 6

Mean + SD = 7.2 + 3.4

Range 3–15

Biochemical tests

All have +ve TRAb/TSI;

4 have +ve TPO/TG Ab

2 have NL TSH, FT4 (Graves’ Eye Disease)

4 ↓TSH,↑FT4, ↑FT3

All had ↓TSH, ↑FT4 &/FT3. 47 had reported TPO/TG Ab; 20 + ve.

22 pts. had reported TRAb/TSI; all –ve.

All had ↑TSH, ↓FT4. TPO/TG Ab reported in 14: all +ve.

4 had ↓ACTH & cortisol.

2 had ↑Glu, +ve GAD65 Ab, & ↓ C-peptide, pH. & ↑A1c

All had ↓TSH, 46↑FT4 /FT3 initially, 3 NL FT4

19 cases had ↑TSH &↓FT4/ FT3.

TPO/TG Ab reported in 28: 19 + ve; TRAb/TSI in 21:1 + ve.33 cases stated just as hypothyroid.

Diagnosis

2 Graves’ eye disease

4 Graves’ disease

3 cases described as “thyroid storm”.

44 had symptoms of hyperthyroidism.

9 were asymptomatic.

11 symptoms not reported

Primary hypothyroidism (biochemically) in all.

14 had symptoms of hypothyroidism.

19 cases had primary hypothyroidism with ↑TSH & ↓FT4/FT3.

Others stated to be hypothyroid with no tests results.

Imaging

MRI, RAI uptake

2 enlarged extraocular muscles; 1 ↑thyroid perfusion,1 ↑RAI uptake. 1 MRI pituitary NL; 1 Not reported.

11 had ↓uptake on thyroid scan; 2 had ↑uptake on PET scan; 14 had thyroid US various findings; 31 not reported.

Thyroid US in 7–1 swollen gland, 6 heterogeneous echo-structure. PET scan in 5 (↑uptake in 3). Not reported in 16.

Not reported during hypothyroid state.

CTCAE grade reported

Not reported in all;.

Grade 2 = 1 and not reported. = 66

Not reported in all 29.

Grade 2 in one;

Not reported in 48.

Therapy at onset at diagnosis

3 high dose steroids; 4 had anti-thyroid drugs(1 had LT4)

36 no treatment for hyperthyroidism;

8 on steroid (1 colitis; 3 adrenal insufficiency; 4 not reported); 16 on β-blockers; 8 had anti-thyroid drugs; 3 had iodine solutions (thyroid storm);

3 not reported.

LT4 = 26; No LT4 = 1;

LT4 Not reported in 2.

Steroids = 3; Insulin = 2.

39 on LT4. 11 not reported.

Outcome

All improved; 2 on LT4 (1 had thyroidectomy; 1 became hypothyroid).

42 required LT4; 17 no LT4; 8 not reported.

23 0n LT4; 3 subclinical hypothyroid; 2 not reported; 1 deceased.

44 on LT4. LT4 not reported in 6.