J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 11, Number 4, April 2019, pages 225-236

Adverse Effects of Immune Checkpoint Inhibitors (Programmed Death-1 Inhibitors and Cytotoxic T-Lymphocyte-Associated Protein-4 Inhibitors): Results of a Retrospective Study

**Table 1.** Summary of Reported IrAEs Involving Gastrointestinal System: UDCA, ENBD
References	Presentation	Number of cases	Age (mean)	Immune checkpoint inhibitors (number of cases)	Doses (mean)	Treatment (outcome)
UDCA: ursodeoxycholic acid; ENBD: endoscopic naso-biliary drainage.
Tubular gastrointestinal tract
[14-27]	Enterocolitis/enteritis/colitis	14	32 - 85 (65)	Pembrolizumab-3, nivolumab-11	1 - 19 (13)	Prednisone/infliximab/mesalazine/budesonide, improved
[28, 29]	Intestinal perforation	2	73, 65	Nivolumab-2	3, 3	Surgical intervention, improved
[30]	Intestinal pseudo-obstruction	1	62	Nivolumab	14	Prednisone, improved
[31]	Esophagitis and gastritis	1	93	Nivolumab	6 mo.	Prednisone, improved
[32]	Hemorrhagic gastritis	1	77	Nivolumab	10	Prednisolone, improved
[33]	Oral mucositis, esophagitis	1	69	Pembrolizumab	14	Methylprednisolone, prednisone, improved
[34]	Intra-abdominal abscess	1	49	Pembrolizumab	5	Abscess drainage, antibiotics, adalimumab, improved
Liver
[35-42]	Hepatitis	11	42 - 80 (61)	Pembrolizumab-5, nivolumab-6	1 - 17 (5)	Methylprednisolone/corticosteroids/prednisone/UDCA/mycophenolate, improved
[40]	Vanishing bile duct syndrome	1	49	Pembrolizumab	1	Prednisolone, UDCA, mycophenolate
[43]	Acute liver failure	1	60	Pembrolizumab	1	Prednisone/deceased
Biliary tract
[44-46]	Cholangitis	5	64 - 82 (75)	Nivolumab-5	4 - 12 (8)	Methylprednisolone/UDCA/stent/prednisone, improved
[47]	Cholecystitis	1	63	Nivolumab	5	stent, ENBD, antibiotics, steroids
Pancreas
[48-52]	Pancreatitis	6	43 - 76 (57)	Pembrolizumab-2, nivolumab-4	2 - 19 (7)	Prednisone/duodenal stent/pancreaticoduodectomy/pancreatic enzymes/dexamethasone, improved

Table 1. Summary of Reported IrAEs Involving Gastrointestinal System: UDCA, ENBD

References

Presentation

Number of cases

Age (mean)

Immune checkpoint inhibitors (number of cases)

Doses (mean)

Treatment (outcome)

UDCA: ursodeoxycholic acid; ENBD: endoscopic naso-biliary drainage.

Tubular gastrointestinal tract

[14-27]

Enterocolitis/enteritis/colitis

32 - 85 (65)

Pembrolizumab-3, nivolumab-11

1 - 19 (13)

Prednisone/infliximab/mesalazine/budesonide, improved

[28, 29]

Intestinal perforation

73, 65

Nivolumab-2

3, 3

Surgical intervention, improved

[30]

Intestinal pseudo-obstruction

Nivolumab

Prednisone, improved

[31]

Esophagitis and gastritis

Nivolumab

6 mo.

Prednisone, improved

[32]

Hemorrhagic gastritis

Nivolumab

Prednisolone, improved

[33]

Oral mucositis, esophagitis

Pembrolizumab

Methylprednisolone, prednisone, improved

[34]

Intra-abdominal abscess

Pembrolizumab

Abscess drainage, antibiotics, adalimumab, improved

Liver

[35-42]

Hepatitis

42 - 80 (61)

Pembrolizumab-5, nivolumab-6

1 - 17 (5)

Methylprednisolone/corticosteroids/prednisone/UDCA/mycophenolate, improved

[40]

Vanishing bile duct syndrome

Pembrolizumab

Prednisolone, UDCA, mycophenolate

[43]

Acute liver failure

Pembrolizumab

Prednisone/deceased

Biliary tract

[44-46]

Cholangitis

64 - 82 (75)

Nivolumab-5

4 - 12 (8)

Methylprednisolone/UDCA/stent/prednisone, improved

[47]

Cholecystitis

Nivolumab

stent, ENBD, antibiotics, steroids

Pancreas

[48-52]

Pancreatitis

43 - 76 (57)

Pembrolizumab-2, nivolumab-4

2 - 19 (7)

Prednisone/duodenal stent/pancreaticoduodectomy/pancreatic enzymes/dexamethasone, improved

**Table 2.** Summary of Reported IrAEs Involving Endocrine System: TSH, TPO Antibodies, TgAb, N/A, GAD, ACTH, DM, and DKA
References	Presentation	Number of cases	Age (mean)	Immune checkpoint inhibitors (number of cases)	Doses (mean)	Labs (number of cases)	Treatments (outcome)
TSH: thyroid-stimulating hormone; TPO: thyroid peroxidase; TgAb: thyroglobulin antibodies; N/A: not available; GAD: glutamic acid decarboxylase; ACTH: adrenocorticotropic hormone; DM: diabetes mellitus; DKA: diabetic ketoacidosis.
Adrenal
	Cortisol	ACTH
[53-63]	ACTH insufficiency	12	39 - 83 (60)	Nivolumab-8, nivolumab/ipilimumab-4	2 - 13 (9)	Low-11 High-1	Low-11 High-1	Hydrocortisone, life long
[64, 65]	Primary adrenal insufficiency	2	43, 55	Pembrolizumab-1, nivolumab-1	4, 10	Low-2	High-2	Hydrocortisone with fludrocortisone, life long
Thyroid
	Free T4	TSH	Antibodies
[61, 65-69]	Thyroiditis followed by hypothyroidism	7	46 - 73 (59)	Pembrolizumab-1, nivolumab-1, nivolumab/ipilimumab-5	1 - 8 (3)	Low-7	High-7	Negative-2, TPO/TgAb-2, TgAb-1, N/A-2	Levothyroxine, life long
[70]	Hypophysitis with central hypothyroidism	1	77	Nivolumab/ipilimumab	5	Low	Low	N/A	Levothyroxine/steroids, life long
[53, 58, 59]	Hypophysitis with primary hypothyroidism	3	54 - 83 (66)	Nivolumab-3	5 - 11 (7)	Low-3	High-3	TPO/TgAb-1, TPO-1, N/A-1	Levothyroxine, life long
[71]	Myxedema crisis	1	53	Nivolumab	N/A	Low	High	N/A	Levothyroxine, life long
[72, 73]	Primary hypothyroidism	2	62, 63	Nivolumab-2	2, 1	Low-1, N/A-1	High-1, WNL-1	TPO/TgAb-1, TPO-1	Levothyroxine, life long
[74]	Thyroid storm	1	24	Nivolumab/ipilimumab	2	High	Low	Negative	Symptomatic treatment and hydrocortisone followed by prednisone
[62]	Thyroiditis followed by central hypothyroidism from hypophysitis	1	53	Nivolumab/ipilimumab	3	Low	Low	Negative	Levothyroxine, life long
[75]	Thyrotoxicosis from thyroiditis	1	55	Nivolumab	2	High	Low	TgAb	Symptomatic treatment
Pancreas
	HbA1c (mean)	Anti-GAD antibodies
[66, 76-80]	Acute type 1 DM	6	58 - 73 (79)	Pembrolizumab-2, pembrolizumab/ipilimumab-1, nivolumab-3	1 - 17 (8)	6.3 - 9.7 (6.6)	Negative-3, positive-3	Insulin injections, insulin dependent
[69, 73, 81-94]	DKA	16	34 - 80 (61)	Pembrolizumab-2, pembrolizumab/ipilimumab-2, nivolumab-8, nivolumab/ipilimumab-4	1 - 20 (6)	6.5 - 10.7 (7.9)	Positive-8, negative-8	Insulin drip followed by multiple insulin injections, insulin dependent
Parathyroid
	Calcium	Parathyroid hormone
[67]	Primary hypoparathyroidism	1	73	Nivolumab/ipilimumab	2	Low	Undetectable	Calcium and vitamin D, long-term calcium and vitamin D supplement

Table 2. Summary of Reported IrAEs Involving Endocrine System: TSH, TPO Antibodies, TgAb, N/A, GAD, ACTH, DM, and DKA

References

Presentation

Number of cases

Age (mean)

Immune checkpoint inhibitors (number of cases)

Doses (mean)

Labs (number of cases)

Treatments (outcome)

TSH: thyroid-stimulating hormone; TPO: thyroid peroxidase; TgAb: thyroglobulin antibodies; N/A: not available; GAD: glutamic acid decarboxylase; ACTH: adrenocorticotropic hormone; DM: diabetes mellitus; DKA: diabetic ketoacidosis.

Adrenal

Cortisol

ACTH

[53-63]

ACTH insufficiency

39 - 83 (60)

Nivolumab-8, nivolumab/ipilimumab-4

2 - 13 (9)

Low-11
High-1

Hydrocortisone, life long

[64, 65]

Primary adrenal insufficiency

43, 55

Pembrolizumab-1, nivolumab-1

4, 10

Low-2

High-2

Hydrocortisone with fludrocortisone, life long

Thyroid

Free T4

TSH

Antibodies

[61, 65-69]

Thyroiditis followed by hypothyroidism

46 - 73 (59)

Pembrolizumab-1, nivolumab-1, nivolumab/ipilimumab-5

1 - 8 (3)

Low-7

High-7

Negative-2, TPO/TgAb-2, TgAb-1, N/A-2

Levothyroxine, life long

[70]

Hypophysitis with central hypothyroidism

Nivolumab/ipilimumab

Low

N/A

Levothyroxine/steroids, life long

[53, 58, 59]

Hypophysitis with primary hypothyroidism

54 - 83 (66)

Nivolumab-3

5 - 11 (7)

Low-3

High-3

TPO/TgAb-1, TPO-1, N/A-1

Levothyroxine, life long

[71]

Myxedema crisis

Nivolumab

N/A

Low

High

N/A

Levothyroxine, life long

[72, 73]

Primary hypothyroidism

62, 63

Nivolumab-2

2, 1

Low-1, N/A-1

High-1, WNL-1

TPO/TgAb-1, TPO-1

Levothyroxine, life long

[74]

Thyroid storm

Nivolumab/ipilimumab

High

Low

Negative

Symptomatic treatment and hydrocortisone followed by prednisone

[62]

Thyroiditis followed by central hypothyroidism from hypophysitis

Nivolumab/ipilimumab

Low

Negative

Levothyroxine, life long

[75]

Thyrotoxicosis from thyroiditis

Nivolumab

High

Low

TgAb

Symptomatic treatment

Pancreas

HbA1c (mean)

Anti-GAD antibodies

[66, 76-80]

Acute type 1 DM

58 - 73 (79)

Pembrolizumab-2, pembrolizumab/ipilimumab-1, nivolumab-3

1 - 17 (8)

6.3 - 9.7 (6.6)

Negative-3, positive-3

Insulin injections, insulin dependent

[69, 73, 81-94]

DKA

34 - 80 (61)

Pembrolizumab-2, pembrolizumab/ipilimumab-2, nivolumab-8, nivolumab/ipilimumab-4

1 - 20 (6)

6.5 - 10.7 (7.9)

Positive-8, negative-8

Insulin drip followed by multiple insulin injections, insulin dependent

Parathyroid

Calcium

Parathyroid hormone

[67]

Primary hypoparathyroidism

Nivolumab/ipilimumab

Low

Undetectable

Calcium and vitamin D, long-term calcium and vitamin D supplement

**Table 3.** Summary of Reported IrAEs Involving Cardiovascular System: EF
References	Presentation	Number of cases	Age (mean)	Immune checkpoint inhibitors (number of cases)	Doses (mean)	Labs	Treatments (outcome)
EF: ejection fraction.
[95-99]	Myocarditis	10	49 - 80 (62)	Nivolumab-2, ipilimumab-5, nivolumab/ipilimumab-4	1 - 10 (3)	Yes-6, no-2, N/A-2	Yes-6, no-2, N/A-2	Cardioversion/steroids/infliximab/pacemaker/beta blockers/diuretics, death-6, EF improved-4
[98, 100]	Cardiac arrest	2	63, 88	Pembrolizumab-1, nivolumab-1	4, 3	Yes-2	Yes-1, N/A-1	Steroids/pacemaker, death-1, clinically improved-1
[98]	Heart failure	1	81	Ipilimumab	3	No	Yes	Diuretics, EF did not improve
[101]	Temponade	1	64	Nivolumab	9	No	N/A	Pericardiocentesis, improved
[98]	Myocardial fibrosis	1	61	Ipilimumab	2	N/A	N/A	Steroids, death
[102]	Cardiac allograft rejection	1	49	Nivolumab	1	Yes	Yes	Steroids/dobutamine, EF improved
[98]	Cardiomyopathy	1	68	Ipilimumab	4	N/A	Yes	Diuretics/ACE inhibitors/beta blocker, EF, improved

Table 3. Summary of Reported IrAEs Involving Cardiovascular System: EF

References

Presentation

Number of cases

Age (mean)

Immune checkpoint inhibitors (number of cases)

Doses (mean)

Labs

Treatments (outcome)

Cardiac enzyme elevation

EF reduction

EF: ejection fraction.

[95-99]

Myocarditis

49 - 80 (62)

Nivolumab-2, ipilimumab-5, nivolumab/ipilimumab-4

1 - 10 (3)

Yes-6, no-2, N/A-2

Cardioversion/steroids/infliximab/pacemaker/beta blockers/diuretics, death-6, EF improved-4

[98, 100]

Cardiac arrest

63, 88

Pembrolizumab-1, nivolumab-1

4, 3

Yes-2

Yes-1, N/A-1

Steroids/pacemaker, death-1, clinically improved-1

[98]

Heart failure

Ipilimumab

Yes

Diuretics, EF did not improve

[101]

Temponade

Nivolumab

N/A

Pericardiocentesis, improved

[98]

Myocardial fibrosis

Ipilimumab

N/A

Steroids, death

[102]

Cardiac allograft rejection

Nivolumab

Yes

Steroids/dobutamine, EF improved

[98]

Cardiomyopathy

Ipilimumab

N/A

Yes

Diuretics/ACE inhibitors/beta blocker, EF, improved

**Table 4.** Summary of Reported IrAEs Involving Pulmonary System
References	Presentation	Number of cases	Age (mean)	Immune checkpoint inhibitors (number of cases)	Doses (mean)	Treatments (outcome)
[103, 103]	Pneumonitis	3	72 - 83 (76)	Nivolumab-3	1 - 8 (4)	Methylprednisolone
[104]	Infusion reaction	1	68	Nivolumab	2	Methylprednisolone
[105]	Acute fibrinous and organizing pneumonia	1	68	Nivolumab	10	Methylprednisolone

Table 4. Summary of Reported IrAEs Involving Pulmonary System

References

Presentation

Number of cases

Age (mean)

Immune checkpoint inhibitors (number of cases)

Doses (mean)

Treatments (outcome)

[103, 103]

Pneumonitis

72 - 83 (76)

Nivolumab-3

1 - 8 (4)

Methylprednisolone

[104]

Infusion reaction

Nivolumab

Methylprednisolone

[105]

Acute fibrinous and organizing pneumonia

Nivolumab

Methylprednisolone

**Table 5.** Summary of Reported IrAEs Involving Renal System: AKI
References	Presentation	Number of cases	Age (mean)	Immune checkpoint inhibitors (number of cases)	Doses (mean)	Labs	Treatments (outcome)
AKI: acute kidney injury.
[106-113]	AKI	16	43 - 78 (67)	Pembrolizumab-5, nivolumab-6, ipilimumab-1, nivolumab/ipilimumab-3, pembrolizumab/nivolumab-1	2 - 5 (3)	Proteinuria-6, hematuria-3, WBC casts-3, granular casts-2, eosinophils-2, normal-1, N/A-2	Interstitial nephritis-10, tubular-interstitial injury-3, IgA nephropathy-1, minimal change disease-1, acute post-infectious glomerulonephritis-1	Steroids, improved AKI-15, hemodialysis-1
[111]	Nephrotic syndrome	1	45	Ipilimumab	4	Proteinuria	Minimal change disease	Corticosteroids, proteinuria improved

Table 5. Summary of Reported IrAEs Involving Renal System: AKI

References

Presentation

Number of cases

Age (mean)

Immune checkpoint inhibitors (number of cases)

Doses (mean)

Labs

Treatments (outcome)

Urine studies

Biopsy

AKI: acute kidney injury.

[106-113]

AKI

43 - 78 (67)

Pembrolizumab-5, nivolumab-6, ipilimumab-1, nivolumab/ipilimumab-3, pembrolizumab/nivolumab-1

2 - 5 (3)

Proteinuria-6, hematuria-3, WBC casts-3, granular casts-2, eosinophils-2, normal-1, N/A-2

Interstitial nephritis-10, tubular-interstitial injury-3, IgA nephropathy-1, minimal change disease-1, acute post-infectious glomerulonephritis-1

Steroids, improved AKI-15, hemodialysis-1

[111]

Nephrotic syndrome

Ipilimumab

Proteinuria

Minimal change disease

Corticosteroids, proteinuria improved