Evan J. Lipson, MD, and Andrew Stolbach, MD, MPH, prepared useful practice aids pertaining to immune-related adverse effects for this CME/MOC/CNE activity titled Best Practices for Recognizing & Managing Immune-Related Adverse Events in the Emergency Department: Become Aware, Stay Alert, Change Your Practice, & Keep Patients With Cancer Safe. For the full presentation, monograph, complete CME/MOC/CNE information, and to apply for credit, please visit us at http://bit.ly/2MVl3DM. CME/MOC/CNE credit will be available until November 26, 2020.

1. Immuno-Oncology 101 for Emergency Physicians
Immune Checkpoint Inhibition in the Treatment of Cancer
Access the activity, “Best Practices for Recognizing & Managing Immune-Related Adverse Events in the
Emergency Department: Become Aware, Stay Alert, Change Your Practice, & Keep Patients With Cancer Safe”
at PeerView.com/RQF40.
PRACTICE AID
APC: antigen-presenting cell; CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte–associated antigen 4; MHC: major histocompatibility complex; PD-1: programmed cell death protein 1;
PD-L1: programmed death ligand 1; TCR: T-cell receptor.
Tumor Microenvironment
Lymphoid Tissue
Immune checkpoint inhibitors modulate T-lymphocyte responses
against cancer by blocking negative regulation of immune responses
PD-1 pathway inhibits
signaling downstream of TCR
• TCR triggered by antigen
presented by tumor cell
• Negative regulatory receptor
PD-1 expressed and PD-L1
reactively expressed
• PD-L1 binds to PD-1
T cell inactivated
T cell inactivated
T cell activated
T cell activated
Anti–PD-1 or anti–PD-L1
monoclonal antibodies
block the interaction and
negative regulation
Anti–CTLA-4 monoclonal
antibodies block negative
regulation by CTLA-4
CTLA-4 is a negative regulator
of costimulation required for
activation of an
antitumor T cell in a lymph
node upon recognition of
tumor antigen
PD-1/PD-L1
Checkpoint
Inhibition
CTLA-4
Checkpoint
Inhibition
FDA-Approved Therapies
FDA-Approved Therapies
Without
Immunotherapy
With
Immunotherapy
MHC
Antigen
TCR
PD-1
PD-L1
Anti–
PD-L1
Anti–
PD-1
Tumor
cell
Tumor escape
Inactivation
of T Cell
Activation
of T Cell
Elimination of
tumor cells
Without
Immunotherapy
With
Immunotherapy
MHC CD80/86
CTLA-4
Anti–
CTLA-4
antibody
APC
Antigen
TCR
Inactivation
of T Cell
Activation
of T Cell
Tumor escape Elimination of
tumor cells
STOP
STOP
GO
GO
GO
Tumor escape
Tumor escape
Tumor attack
Tumor attack
Anti–PD-1: Nivolumab
Pembrolizumab
Cemiplimab-rwlc
Anti–CTLA-4: Ipilimumab
Anti–PD-L1: Atezolizumab
Avelumab
Durvalumab
• Proteins on T cells or cancer cells that need to be activated/inactivated to start/stop
an immune response (eg, PD-1, PD-L1, CTLA-4)
• Serve as “brakes” that help keep immune responses in check; can prevent T-cell response
against cancer cells
• Can be blocked by immune checkpoint inhibitors (the “brakes” on the immune system are
released and T cells are able to attack and kill cancer cells)
What Are
Immune
Checkpoints?

2. Immuno-Oncology 101 for Emergency Physicians
Immune-Related Adverse Events in Patients With Cancer
Access the activity, “Best Practices for Recognizing Managing Immune-Related Adverse Events in the
Emergency Department: Become Aware, Stay Alert, Change Your Practice, Keep Patients With Cancer Safe”
at PeerView.com/RQF40.
PRACTICE AID
What Are irAEs?
• Immune checkpoint inhibitors are associated with important clinical benefits, but general
immunologic enhancement can also lead to a unique spectrum of immune-related adverse
events (irAEs)
• Pathophysiology of irAEs is not entirely clear, but T-cell, antibody, and cytokine responses
may be involved
• irAEs differ significantly from toxicities of chemotherapies and other cancer therapies
• Any organ system can be affected, but more commonly occurring irAEs are pulmonary
(pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo), gastrointestinal (diarrhea,
enterocolitis, transaminitis, hepatitis, pancreatitis), and endocrine (thyroiditis, hypophysitis,
adrenal insufficiency) irAEs
• irAEs can have unpredictable onset and can present at any time, but typically start within the
first few weeks to months after treatment initiation and can occur after treatment discontinuation
• irAEs can be difficult to differentiate from other etiologies and are often diagnosed by exclusion;
other causes should be ruled out, but immunotherapy-related toxicity should always be included
in the differential for patients who are receiving or have received immunotherapies
Musculoskeletal
Gastrointestinal
Renal
Hematologic
Neurologic
Pulmonary
Cardiovascular
Ocular
Dermatologic
Endocrine
Spectrum of Potential irAEs
Neuropathy, meningitis,
Guillain–Barré syndrome,
myasthenia gravis, encephalitis,
and transverse myelitis
Myocarditis, pericarditis,
arrhythmias, impaired ventricular
function with heart failure and
vasculitis, and venous
thromboembolism
Pneumonitis
Colitis, hepatitis, and hepatic
transaminases
Inflammatory arthritis, myositis,
and polymyalgia-like syndrome
Uveitis/iritis, episcleritis, and blepharitis
Primary hypothyroidism,
hyperthyroidism, hypophysitis,
primary adrenal insufficiency,
and diabetes
Rash/inflammatory dermatitis,
bullous dermatoses, and severe
cutaneous adverse reactions
Autoimmune hemolytic anemia,
aTTP, hemolytic uremic syndrome,
aplastic anemia, lymphopenia, ITP,
and acquired hemophilia
Nephritis

3. Immuno-Oncology 101 for Emergency Physicians
Immune-Related Adverse Events in Patients With Cancer
Access the activity, “Best Practices for Recognizing Managing Immune-Related Adverse Events in the
Emergency Department: Become Aware, Stay Alert, Change Your Practice, Keep Patients With Cancer Safe”
at PeerView.com/RQF40.
PRACTICE AID
Change How You Approach the Evaluation, Diagnosis, and Management
of Patients With Cancer in the Emergency Department!
Ask about
history of cancer
treatment, including
immunotherapy,
from any patient with
cancer presenting to
an ED in an acutely
unwell state
Call the oncology care
provider for any
moderate or severe
(grade 2 or higher)
toxicity upon
presentation to
discuss treatment
history, if toxicity
could be caused by
immunotherapy, and
next steps
Patients receiving
immunotherapies are
often given wallet
cards listing their
therapies à ask
about that
Simplify treatment
decisions à consider
corticosteroids for
frontline management
of immune-related
toxicities in most cases
Coordinate with the
oncology care provider
and other specialists,
if possible
Modify your
differential diagnosis
when a patient has
received cancer
immunotherapy à
almost any
inflammatory condition
could be caused by
immune checkpoint
inhibitor therapy
Avoid premature
closure
A multidisciplinary approach can boost the collective awareness
of irAEs and help keep patients safe!
History
Consultation
Diagnosis
Management

4. Immuno-Oncology 101 for Emergency Physicians
Immune-Related Adverse Events in Patients With Cancer
Access the activity, “Best Practices for Recognizing Managing Immune-Related Adverse Events in the
Emergency Department: Become Aware, Stay Alert, Change Your Practice, Keep Patients With Cancer Safe”
at PeerView.com/RQF40.
PRACTICE AID
General Recommendations for Grading,
Assessment, and Management of irAEs1
irAEs are often
diagnosed by exclusion;
other causes should
be ruled out (including
AEs of other
therapies used), but
immunotherapy-related
toxicity should always be
included in the differential
There should be a high
level of suspicion that
new symptoms are
treatment related; early
recognition, evaluation,
and treatment of irAEs
plus patient education
are essential for the
best outcome
Depending on the
severity of an irAE,
management
may require
corticosteroids or other
immunosuppressive
treatment and
interruption or
discontinuation
of therapy
If appropriate
immunosuppressive
treatment is
used, patients generally
recover from irAEs
Grade 1 Asymptomatic; diagnostic changes only; continue immunotherapy
Grade 2
Mild-to-moderate symptoms; grade 2 diagnostic abnormalities
• Hold treatment; provide supportive care
• Methylprednisolone 0.5-1.0 mg/kg/d until stable (or oral equivalent)
If improving: transition to oral steroid at start of taper
• Dose suggested: 60 mg prednisone daily x 2 wk
• Taper over 4 wk or more to reduce recurrence of symptoms
• May consider reinitiation of immunotherapy
If progressing: treat as grade 3/4
• Consider hospitalization of patient; multidisciplinary evaluation
of toxicity
Grade 3/4
Discontinue immunotherapy (consider organ-specific algorithms; endocrine)
• Hospitalization indicated
• Methylprednisolone 1.0-2.0 mg/kg/d until stable
Refractory
If no improvement or progression, additional immunosuppressant treatment may be
needed
• Infliximab 5 mg/kg (except if contraindicated)
• Mycophenolate mofetil 1 g twice daily
• Cyclosporine or IV immunoglobulin
Grade Assessment and Management

5. Immuno-Oncology 101 for Emergency Physicians
Immune-Related Adverse Events in Patients With Cancer
Access the activity, “Best Practices for Recognizing Managing Immune-Related Adverse Events in the
Emergency Department: Become Aware, Stay Alert, Change Your Practice, Keep Patients With Cancer Safe”
at PeerView.com/RQF40.
PRACTICE AID
Organ-Specific Summary of Presentation,
Assessment, and Management of irAEs1
Pneumonitis
SOB, DOE, cough,
wheezing, chest pressure,
increased oxygen
requirement, hypoxia,
and tachycardia
O2
saturation levels, CT of
chest; rule out progression of
disease, lymphangitic spread,
pulmonary embolism, and
pleural effusion
O2
support, bronchoscopy ±
BAL, steroids, and
antibiotic prophylaxis
Colitis
Abdominal cramping or pain,
loose stools, and altered
frequency of stools
Rule out infectious causes;
stool cultures; rule out
perforation; abdominal CT
and lactoferrin and
calprotectin levels
If steroid refractory:
infliximab; antispasmodic,
antidiarrheal, and
fluid support
Rash/skin
Macules, papules,
morbilliform, pruritus,
eczema, psoriasis, vitiligo,
bullous pemphigoid,
Stevens-Johnson syndrome,
and TEN syndrome
Rule out other causes; total
body exam (include mucous
membranes); measure
distribution and skin biopsy
Topical moderate-to-high–
dose steroids; IV steroids;
consult dermatology and
infectious disease; if
mucosa, consult gynecology,
ophthalmology, and urology;
admission: burn unit
Endocrine—
adrenal
insufficiency
Nonspecific fatigue,
sluggishness, anorexia,
weight change, irritability,
and feeling hot or cold
More common with anti–PD-1;
monitor ACTH and cortisol
Corticosteroids (must start
prior to any other hormone
replacement) and stress
dosing in trauma
Endocrine—
hypophysitis
Headache, fatigue, and
visual changes
CMP, glucose, cortisol, ACTH,
pituitary panel (TSH, FSH,
LH, ACTH, and prolactin);
testosterone/estradiol; and
MRI of brain with sellar cuts
Hormone replacement
Endocrine—
hyperthyroidism
Tachycardia and irritability Monitor TSH and T4
Antithyroid: methimazole;
beta-blockers
Endocrine—
hypothyroidism
Severe fatigue, sluggishness,
anorexia, and weight gain
Monitor TSH and T4
Levothyroxine;
usually permanent
Endocrine—
type 1 diabetes
Thirst, psychosis, and
change in level of
consciousness
Blood glucose Insulin
System Signs Symptoms Assessment Management

6. Immuno-Oncology 101 for Emergency Physicians
Immune-Related Adverse Events in Patients With Cancer
Access the activity, “Best Practices for Recognizing Managing Immune-Related Adverse Events in the
Emergency Department: Become Aware, Stay Alert, Change Your Practice, Keep Patients With Cancer Safe”
at PeerView.com/RQF40.
PRACTICE AID
ALK: alkaline phosphatase; ANA: antinuclear antibodies; aTTP: acquired thrombotic thrombocytopenic purpura; BAL: broncho-alveolar lavage; CCP: cyclic citrullinated peptide; CK: creatinine kinase;
CMP: comprehensive metabolic panel; CRF: corticotropin-releasing factor; CRP: C-reactive protein; CXR: chest X-ray; DOE: dyspnea on exertion; EMG: electromyography; ESR: erythrocyte sedimentation
rate; FSH: follicle-stimulating hormone; irAE: immune-related adverse event; ITP: immune thrombocytopenia; LH: luteinizing hormone; LP: lumbar puncture; OT: occupational therapy; PD-1: programmed
cell death protein 1; PT: physical therapy; RF: rheumatoid factor; RUQ: right upper quadrant; SOB: shortness of breath; TEN: toxic epidermal necrolysis.
1. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf.
Accessed October 14, 2019.
Organ-Specific Summary of Presentation,
Assessment, and Management of irAEs1
(Cont’d)
Note: This irAE list is not all inclusive
Hepatic
Nausea, vague abdominal
discomfort, RUQ pain,
dehydration, jaundice,
bleeding, bruising, dark skin,
and drowsiness
Liver enzymes (AST, ALT,
ALK, total and direct bilirubin),
liver ultrasound, GI consult,
and rule out viral syndrome
Hold hepatotoxic drugs;
mycophenolate 2 mg/kg/d;
if refractory: no infliximab
Renal/nephritis
Elevated serum creatinine,
vague nausea, emesis,
decreased urine output,
blood in urine, and
ankle swelling
Serum creatinine and
urinalysis; nephrology consult,
renal ultrasound, and biopsy
Limit nephrotoxic drugs,
antibiotics, NSAIDs, and
contrast dye; identify
high-risk patients (CRF);
and hydration
Cardiac
Chest pain, SOB,
tachycardia, arrhythmias,
VTE, fluid retention,
pericarditis, myocarditis,
effusion, and vasculitis
ECG, echocardiogram, CXR,
and cardiology consult
Blood pressure support
and heart rate regulation
Neurologic
Unusual weakness,
numbness, peripheral
neuropathy, autonomic
neuropathy, altered gait,
memory difficulties,
seizures, aseptic meningitis,
myasthenia gravis,
Guillain-Barré, encephalitis,
and transverse myelitis
Neurology consult, MRI of
brain to rule out CVA and brain
metastases; MRI spine; LP;
rule out infection
Permanent discontinuation;
rehab services;
IV immunoglobulin
Ocular
Dry, scratchy eyes;
vision changes; redness;
inflammation; pain;
iritis; uveitis; blepharitis;
episcleritis; and conjunctivitis
Rule out infection and consult
with ophthalmology
Lubricating eye drops;
topical corticosteroid eye
drops; decrease local
irritants: contact lens,
eye makeup, etc.
Musculoskeletal
Inflammatory arthritis,
myositis, and
polymyalgia-like syndrome
Rheumatologic tests:
autoimmune panel (ANA,
RF, anti-CCP, ESR, CK, and
CRP); imaging and EMG
NSAIDs, corticosteroid
joint injections, DMARDs,
methotrexate, and PT/OT
System Signs Symptoms Assessment Management