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

Tables

Table 1. Summary of Reported IrAEs Involving Gastrointestinal System: UDCA, ENBD
 
ReferencesPresentationNumber of casesAge (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/colitis1432 - 85 (65)Pembrolizumab-3, nivolumab-111 - 19 (13)Prednisone/infliximab/mesalazine/budesonide, improved
  [28, 29]Intestinal perforation273, 65Nivolumab-23, 3Surgical intervention, improved
  [30]Intestinal pseudo-obstruction162Nivolumab14Prednisone, improved
  [31]Esophagitis and gastritis193Nivolumab6 mo.Prednisone, improved
  [32]Hemorrhagic gastritis177Nivolumab10Prednisolone, improved
  [33]Oral mucositis, esophagitis169Pembrolizumab14Methylprednisolone, prednisone, improved
  [34]Intra-abdominal abscess149Pembrolizumab5Abscess drainage, antibiotics, adalimumab, improved
Liver
  [35-42]Hepatitis1142 - 80 (61)Pembrolizumab-5, nivolumab-61 - 17 (5)Methylprednisolone/corticosteroids/prednisone/UDCA/mycophenolate, improved
  [40]Vanishing bile duct syndrome149Pembrolizumab1Prednisolone, UDCA, mycophenolate
  [43]Acute liver failure160Pembrolizumab1Prednisone/deceased
Biliary tract
  [44-46]Cholangitis564 - 82 (75)Nivolumab-54 - 12 (8)Methylprednisolone/UDCA/stent/prednisone, improved
  [47]Cholecystitis163Nivolumab5stent, ENBD, antibiotics, steroids
Pancreas
  [48-52]Pancreatitis643 - 76 (57)Pembrolizumab-2, nivolumab-42 - 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
 
ReferencesPresentationNumber of casesAge (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
CortisolACTH
  [53-63]ACTH insufficiency1239 - 83 (60)Nivolumab-8, nivolumab/ipilimumab-42 - 13 (9)Low-11
High-1
Low-11
High-1
Hydrocortisone, life long
  [64, 65]Primary adrenal insufficiency243, 55Pembrolizumab-1, nivolumab-14, 10Low-2High-2Hydrocortisone with fludrocortisone, life long
Thyroid
Free T4TSHAntibodies
  [61, 65-69]Thyroiditis followed by hypothyroidism746 - 73 (59)Pembrolizumab-1, nivolumab-1, nivolumab/ipilimumab-51 - 8 (3)Low-7High-7Negative-2, TPO/TgAb-2, TgAb-1, N/A-2Levothyroxine, life long
  [70]Hypophysitis with central hypothyroidism177Nivolumab/ipilimumab5LowLowN/ALevothyroxine/steroids, life long
  [53, 58, 59]Hypophysitis with primary hypothyroidism354 - 83 (66)Nivolumab-35 - 11 (7)Low-3High-3TPO/TgAb-1, TPO-1, N/A-1Levothyroxine, life long
  [71]Myxedema crisis153NivolumabN/ALowHighN/ALevothyroxine, life long
  [72, 73]Primary hypothyroidism262, 63Nivolumab-22, 1Low-1, N/A-1High-1, WNL-1TPO/TgAb-1, TPO-1Levothyroxine, life long
  [74]Thyroid storm124Nivolumab/ipilimumab2HighLowNegativeSymptomatic treatment and hydrocortisone followed by prednisone
  [62]Thyroiditis followed by central hypothyroidism from hypophysitis153Nivolumab/ipilimumab3LowLowNegativeLevothyroxine, life long
  [75]Thyrotoxicosis from thyroiditis155Nivolumab2HighLowTgAbSymptomatic treatment
Pancreas
HbA1c (mean)Anti-GAD antibodies
  [66, 76-80]Acute type 1 DM658 - 73 (79)Pembrolizumab-2, pembrolizumab/ipilimumab-1, nivolumab-31 - 17 (8)6.3 - 9.7 (6.6)Negative-3, positive-3Insulin injections, insulin dependent
  [69, 73, 81-94]DKA1634 - 80 (61)Pembrolizumab-2, pembrolizumab/ipilimumab-2, nivolumab-8, nivolumab/ipilimumab-41 - 20 (6)6.5 - 10.7 (7.9)Positive-8, negative-8Insulin drip followed by multiple insulin injections, insulin dependent
Parathyroid
CalciumParathyroid hormone
  [67]Primary hypoparathyroidism173Nivolumab/ipilimumab2LowUndetectableCalcium and vitamin D, long-term calcium and vitamin D supplement

 

Table 3. Summary of Reported IrAEs Involving Cardiovascular System: EF
 
ReferencesPresentationNumber of casesAge (mean)Immune checkpoint inhibitors (number of cases)Doses (mean)LabsTreatments (outcome)
Cardiac enzyme elevationEF reduction
EF: ejection fraction.
[95-99]Myocarditis1049 - 80 (62)Nivolumab-2, ipilimumab-5, nivolumab/ipilimumab-41 - 10 (3)Yes-6, no-2, N/A-2Yes-6, no-2, N/A-2Cardioversion/steroids/infliximab/pacemaker/beta blockers/diuretics, death-6, EF improved-4
[98, 100]Cardiac arrest263, 88Pembrolizumab-1, nivolumab-14, 3Yes-2Yes-1, N/A-1Steroids/pacemaker, death-1, clinically improved-1
[98]Heart failure181Ipilimumab3NoYesDiuretics, EF did not improve
[101]Temponade164Nivolumab9NoN/APericardiocentesis, improved
[98]Myocardial fibrosis161Ipilimumab2N/AN/ASteroids, death
[102]Cardiac allograft rejection149Nivolumab1YesYesSteroids/dobutamine, EF improved
[98]Cardiomyopathy168Ipilimumab4N/AYesDiuretics/ACE inhibitors/beta blocker, EF, improved

 

Table 4. Summary of Reported IrAEs Involving Pulmonary System
 
ReferencesPresentationNumber of casesAge (mean)Immune checkpoint inhibitors (number of cases)Doses (mean)Treatments (outcome)
[103, 103]Pneumonitis372 - 83 (76)Nivolumab-31 - 8 (4)Methylprednisolone
[104]Infusion reaction168Nivolumab2Methylprednisolone
[105]Acute fibrinous and organizing pneumonia168Nivolumab10Methylprednisolone

 

Table 5. Summary of Reported IrAEs Involving Renal System: AKI
 
ReferencesPresentationNumber of casesAge (mean)Immune checkpoint inhibitors (number of cases)Doses (mean)LabsTreatments (outcome)
Urine studiesBiopsy
AKI: acute kidney injury.
[106-113]AKI1643 - 78 (67)Pembrolizumab-5, nivolumab-6, ipilimumab-1, nivolumab/ipilimumab-3, pembrolizumab/nivolumab-12 - 5 (3)Proteinuria-6, hematuria-3, WBC casts-3, granular casts-2, eosinophils-2, normal-1, N/A-2Interstitial nephritis-10, tubular-interstitial injury-3, IgA nephropathy-1, minimal change disease-1, acute post-infectious glomerulonephritis-1Steroids, improved AKI-15, hemodialysis-1
[111]Nephrotic syndrome145Ipilimumab4ProteinuriaMinimal change diseaseCorticosteroids, proteinuria improved