Immune-related adverse events-A case-based Approach

REVIEW
published: 20 June 2019

doi: 10.3389/fonc.2019.00530
Immune-Related Adverse Events: A

Case-Based Approach
Caoilfhionn Connolly 1 , Kalindi Bambhania 2 and Jarushka Naidoo 2,3*
1
Department of Internal Medicine, Johns Hopkins Hospital, Baltimore, MD, United States, 2 Department of Oncology, Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, United States, 3 Department of
Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, United States
Immunotherapy has heralded the advent of a new era in oncology. Immune checkpoint
inhibitors (ICIs) enhance anti-tumor immunity, thereby reinvigorating a patient’s immune
system to fight cancer. While therapy with this class of agents has resulted in
improved clinical outcomes for patients with multiple tumor types, a broad spectrum
of immune-related adverse events (irAEs) may affect any organ system, with variable
clinical presentations. Prompt recognition and management of irAEs are associated
with improved irAE outcomes, and represents an important new clinical challenge
for practicing oncologists. Herein, we provide a comprehensive case-based review of
the most common and clinically-important irAEs, focussing on epidemiology, clinical
manifestations, and management. We also examine future strategies that may provide
meaningful insights into the prevention and management of irAEs.
Edited by:
Keywords: immune checkpoint inhibitors, immune-related adverse events, immunotherapy, immune-related
Joshua Michael Bauml,
toxicities, management
University of Pennsylvania,
United States
Reviewed by:
Sandip Patel,
INTRODUCTION
University of California, San Diego,
United States
Immune evasion is one of the hallmarks of cancer cells (1). Immune checkpoints are negative
Giulio Metro, regulators of immune activation; exploiting the action of checkpoints such as cytotoxic T-
Hospital of Santa Maria della lymphocyte antigen 4 (CTLA-4), programmed cell death (PD-1), and its ligand programmed
Misericordia in Perugia, Italy cell death ligand 1 (PDL-1) allows cancer cells to evade immune-surveillance, thus enabling
*Correspondence: unchecked tumor growth. Immune checkpoint inhibitors (ICIs) negate this key mechanism of
Jarushka Naidoo cancer progression, revitalizing the immune system to eradicate cancer cells. However, unleashing
jnaidoo1@jhmi.edu the effects of the immune system in this manner can result in a unique spectrum of toxicities
known as immune-related adverse events (irAEs). ICIs have demonstrated unprecedented response
Specialty section: rates in a wide array of cancer types, with seven checkpoint inhibitors currently approved by
This article was submitted to the FDA and in over 14 different cancer treatment indications (Table 1). As ICIs enter routine
Thoracic Oncology,
clinical practice, clinicians across all sub-specialties are increasingly faced with the diagnostic and
a section of the journal
therapeutic challenge of irAE identification and management.
Frontiers in Oncology
The incidence of irAEs has been reported to range from 15 to 90% in late phase clinical studies
Received: 02 April 2019
(2, 3). The risk, clinical manifestations, and severity of irAEs is variable across ICI regimen and
Accepted: 31 May 2019
cancer type. The frequency and severity of irAEs appears greatest amongst patients receiving
Published: 20 June 2019
ipilimumab/nivolumab combination therapy compared to monotherapy (4–6). Patients receiving
Citation:
CTLA-4 therapy more commonly present with colitis and hypophysitis, while patients receiving
Connolly C, Bambhania K and
Naidoo J (2019) Immune-Related
PD-1 therapy more commonly present with pneumonitis and thyroiditis (7–9).
Adverse Events: A Case-Based It is widely recognized that effective management of irAE is dependent on early recognition
Approach. Front. Oncol. 9:530. and prompt intervention (10). High clinical suspicion, timely evaluation and multi-disciplinary
doi: 10.3389/fonc.2019.00530 management provide the foundation for optimal clinical outcomes (Figure 1).
Frontiers in Oncology | www.frontiersin.org 1 June 2019 | Volume 9 | Article 530

Connolly et al. Immune-Related Adverse Events: A Clinical Review
The severity of adverse events can be graded as per all TABLE 1 | FDA-approved ICIs and their indications.
adverse events, utilizing the Common Terminology Criteria for
Drug Initial Therapeutic Indication
Adverse Events (CTCAE) (Table 2) (11). While this grading approval target
system has been used in oncology for many years, this is not
specifically tailored toward irAEs, and should be supplemented Atezolizumab 2016 PD-L1 Non-small-cell carcinoma
by clinical judgement by those familiar with irAEs. In response Urothelial carcinoma
to the clinical need to recognize and manage this class of Avelumab 2017 PD-L1 Merkel cell carcinoma
toxicities, comprehensive guidelines to facilitate appropriate Urothelial cell carcinoma
evaluation and management of irAEs were recently published Cemiplimab 2018 PD-L1 Cutaneous Squamous cell carcinoma
by key oncology societies, including the American Society Durvalumab 2017 PD-L1 Urothelial carcinoma
Non-small cell carcinoma
of Clinical Oncology (ASCO), the European Society for
Ipilimumab 2011 CTLA-4 Melanoma
Medical Oncology (ESMO), the Society for Immunotherapy of
Nivolumab 2014 PD-1 Classical Hodgkin lymphoma
Cancer Toxicity Management Working Group and the National
Hepatocellular carcinoma
Comprehensive Cancer Network (11–13). These guidelines are Melanoma
largely based on retrospective data and expert opinion. While Microsatellite instability-high (MSI-H)
they detail commonly encountered irAEs, rarer toxicities are not or mismatch-repair deficient (dMMR)
universally featured, and there is a paucity of guidance regarding CRC
Non-small cell lung cancer
severe or refractory irAEs, or those in which little has been
Renal cell carcinoma
published. Importantly, a recent meta-analysis demonstrated Small cell lung cancer
that fulminant irAEs resulting in patient death have been Squamous cell carcinoma of head
reported at a rate of 0.3–1.3% (14). Fulminant presentations and neck
are particularly challenging, and in the absence of prospective Urothelial carcinoma
clinical data, management remains variable. While management Pembrolizumab 2014 PD-1 Cervical cancer
Classical Hodgkins lymphoma
varies according to severity of encountered irAE, ICI therapy
Gastric or Gastroesophageal junction
can be continued for most grade 1 toxicities, with suspension adenocarcinoma
of ICI for grade 2 or greater toxicities. Resumption of therapy Hepatocellular carcinoma
following resolution of symptoms is a frequent clinical scenario Melanoma
that is currently lacking data. Retreatment can be considered for MSI-H or dMMR solid tumors
Non-small cell lung carcinoma
grade 2 or 3 toxicities when symptoms revert to grade 1 or less, Squamous cell lung carcinoma
however, permanent discontinuation of therapy is recommended Primary Mediastinal Large B-Cell
with grade 4 irAEs (10, 12, 13). In a recent study of patients Lymphoma
with NSCLC, retreatment with anti-PD-L1 therapy resulted in Squamous cell carcinoma of head
recurrence of irAEs in 52% of patients (15). The safety and benefit and neck
Urothelial carcinoma
of retreatment is unknown and the decision to retreat should be
Ipilimumab and 2015 CTLA-4/PD-1 Melanoma
considered on a case-by case basis. Nivolumab MSI-H or dMMR colorectal carcinoma
This review provides a practical guide to what is known combination
about irAEs and how to optimize evaluation and management Renal cell carcinoma
of irAE utilizing a case-based approach. Within common or rare NSCLC
but clinically-important cases, we highlight the current state- PD-1, programmed cell death protein; PD-L1, programmed cell death ligand-1; CTLA-4,
of the art in terms of diagnosis and management, as well as cytotoxic T lymphocyte-associated antigen 4.
emerging challenges. Finally, we discuss new therapies and novel
approaches that may alleviate the future burden of irAE.
Arthralgia and inflammatory arthritis (IA) are the most
ORGAN-SPECIFIC IRAES commonly encountered rheumatic irAEs (16, 17). ICI-induced
IA can have a variable timing, with a median onset 5 months
Given the wide array of clinical manifestations of irAEs, we (range 1–24 months) after ICI initiation (18). The clinical
summarize the diagnosis, management and emerging data in the presentations of IA are variable with oligoarthritis, polyarthritis,
most common or clinically-challenging irAEs that clinicians may and reactive arthritis-like manifestations being described (19).
encounter by organ system. Figure 2 illustrates some of the irAE Cappelli et al. reported that patients who received combination
manifestations encountered at the Johns Hopkins Hospital. ICIs were more likely to present with large joint involvement
and to already have another irAE, while patients treated with
RHEUMATIC ICI monotherapy were more likely to have initial small joint
involvement and to have IA as their only irAE (16). Other
Case 1: Inflammatory Arthritis rheumatic irAEs include polymyalgia-like syndrome, vasculitis,
Clinical Presentation: A 58-year old woman is treated with sicca syndrome, and inflammatory myopathies (20). The data
combination Ipilimumab/Nivolumab therapy for stage IV regarding the incidence of rheumatic complications is highly
non-small-cell lung carcinoma (NSCLC), and presents with a variable, with rates of arthralgia ranging from 1 to 43%,
3-week history of a left, swollen, and painful left knee. with reports of other manifestations ranging from 0.7 to

FIGURE 1 | Early diagnosis and multidisciplinary management are integral to optimal clinical outcomes. It is crucial that physicians have a detailed knowledge of the
wide range of clinical manifestations of irAEs, as well as familiarity with existing algorithms for their grading and management.
TABLE 2 | Common terminology criteria for adverse events grading.
CTCAE grade Level of care Management ICI therapy
1: Asymptomatic or Mild Ambulatory Observation Continue ICI therapy with close

monitoring
2: Moderate Ambulatory Systemic corticosteroids (0.5–1 mg/kg/day of prednisone or Temporarily hold; resume when grade
equivalent) 1 or less
3: Severe but not Inpatient High dose systemic corticosteroids (1–2 mg/kg/d prednisone Temporarily hold; resume when grade
immediately life-threatening or methylprednisolone); consider additional therapies if no 1 or less in discussion with patient
response with 48–72 h
4: Life-threatening Inpatient +/– intensive High-dose corticosteroids (1–2 mg/kg/d prednisone or Permanent discontinuation with the
care unit methylprednisolone); consider additional therapies if no exception of endocrinopathies
response with 48–72 h managed by hormone replacement
5.1% (21, 22). This is potentially related to the variability with grade 2 IA, ICI was temporarily held while she received
in potential coding of these events in clinical trials, using treatment with acetaminophen, NSAIDs and oral corticosteroids
CTCAE criteria. of prednisone 20 mg/day for 4 weeks. Given large joint
involvement, she also received an intra-articular corticosteroid
Diagnostic Evaluation injection. Corticosteroid dose can be adjusted pending clinical
Patients should undergo a full musculoskeletal evaluation. response with taper over 4–6 weeks in the instance of clinical
Laboratory studies including ESR (Erythrocyte sediment rate), improvement, or, in presence of progressive IA, treatment can be
CRP (C-reactive protein), RF (rheumatoid factor), ACPA (anti- escalated with addition of other immunomodulatory medications
citrullinated peptide/protein antibodies), ANA (anti-nuclear such synthetic or biologic disease-modifying anti rheumatic
antibody), and HLA-B27 (Human Leukocyte Antigen B-27) drugs (DMARDs). This patient demonstrated improvement and
should be sent, to help differentiate between phenotypes of prednisone was tapered over 4 weeks. Ipilimumab/Nivolumab
IA that may have treatment implications. The majority of therapy was resumed when IA symptom control was reached,
patients are seronegative, but a seropositive subgroup has been and the patient was taking a prednisone dose of 10 mg daily. A
described (16). Imaging including joint ultrasound or MRI notable feature of rheumatic irAEs, in particular ICI-induced-
should be completed to assess for effusion, erosive disease and IA, is their predilection for persistence despite cessation of
tenosynovitis. In the above patient, diagnostic evaluation was ICI therapy which may require long-term immunomodulatory
notable for left knee effusion (see Figure 2A) with unremarkable therapy for months to years after diagnosis (23). Due to
synovial fluid analysis, elevated inflammatory markers, and likely prolonged treatment requirements, physicians should
seronegative disease. consider starting immunomodulatory medications earlier than
one would with other irAEs. DMARDs should be considered
Management in all patients with grade 3 or 4 disease, as well as grade 2
Early recognition of IA is critical to avoid erosive joint damage. patients that display progression of disease with corticosteroid
ICI can be continued for grade 1 toxicities and treated with therapy. In steroid-refractory cases, a common approach is to
simple analgesia consisting of acetaminophen and non-steroidal start with Methotrexate, with escalation to biologic agents such
anti-inflammatory drugs (NSAIDs). However, in this patient as infliximab in the absence of adequate clinical response.

FIGURE 2 | Clinical manifestations of irAE. (A) Inflammatory arthritis: US image of knee effusion; (B) myopericarditis: cardiac MRI with late gadolinium enhancement
overlying basal left ventricular lateral wall (arrow); (C) bullous pemphigoid; (D) lichenoid dermatitis; (E) encephalitis: brain MRI with hyperenhancement of right
hippocampus (arrow); (F) pneumonitis: chest CT with bilateral lower lobe infiltrates; (G) colitis: endoscopic findings of pan-colitis.
Case 2: Temporal Arteritis should not delay treatment. In this patient, physical examination
Clinical Presentation: A 76-year old man with advanced urothelial was notable for temporal artery tenderness with intact vision.
presents with temporal headache and jaw claudication 10 days Initial investigations were notable for markedly elevated
after cycle two of durvalumab. ESR and CRP.
Both polymyalgia-like syndrome and giant cell arteritis (GCA)
have been reported following treatment with ICI. A recent
Management
analysis of WHO’s VigiBase found that patients who received
Given intact vision, the patient was commenced on prednisone
ICI had a reporting odds ratio of GCA 13 times greater than
60 mg/day to complete 2 weeks of therapy followed by
patients not treated with ICI (24). This study also reported that
a taper every 2 weeks. Durvalumab was held pending
the median time of onset from last dose of ICI was 55 days (range:
clinical response. Temporal artery biopsy confirmed the
21–98) with a greater predilection for elderly patients, Caucasian
diagnosis. This management was instituted with the input of a
patients, and those with melanoma (24). ICI-induced GCA
rheumatology consult.
symptoms mirror those of traditional GCA, including temporal
Patients with suspected ICI-induced GCA should be managed
headache, jaw claudication, monocular vision loss, unexplained
as per traditional rheumatic GCA with the addition that
fever, and fatigue.
ICI therapy should be held pending clinical improvement in
GCA. In patients without visual loss at diagnosis, treatment
Diagnostic Evaluation should comprise prednisone 1 mg/kg/day (maximum dose of
Early diagnosis is vital to prevent devastating ocular and 60 mg daily). Patients with threatened or established visual
cerebrovascular complications of GCA. Visual impairment has loss at diagnosis should be commenced on intravenous pulse
been reported in 28% of patients with ICI-induced GCA corticosteroids (1 g methylprednisolone daily) for 3 days followed
(24). The diagnosis of GCA should not be made based upon by high dose oral therapy (25). Oral corticosteroids should be
symptoms alone and investigations including complete blood maintained for 2–4 weeks followed by a two-weekly interval
count (CBC), ESR, and CRP. Temporal artery biopsy is the gold taper. Typically, prednisone will be tapered by 10 mg every 2
standard diagnostic test and provides definitive diagnosis, but weeks until a dose of 40 mg/day is reached, at which point the

dose will be reduced by 5 mg decrements every 2 weeks until All grades of cardiac toxicity warrant evaluation given the
a dose of 20 mg/day is reached. At this point, the rate of the risk of cardiac compromise. Effective management requires
corticosteroid taper is slowed. close monitoring with a multimodal therapeutic plan consisting
In the case of relapsed GCA symptoms despite high-dose of ICI cessation, high-dose corticosteroids (1–2 mg/kg of
corticosteroids, abatacept has demonstrated efficacy (26), while prednisone/day or equivalent) and early cardiology consultation
methotrexate and tocilizumab are alternate therapeutic options. with management of cardiac complications. Steroid-refractory
Resumption of ICI therapy can be considered once prednisone cases may necessitate the addition of mycophenolate, infliximab,
dose is <10 mg/day, ideally in consultation with rheumatology. or anti-thymocyte globulin, and there are no specific data
that demonstrate a superior approach of these three options.
Conduction disease is emerging as a common and potentially
CARDIOVASCULAR serious cause of ICI-medicated sudden death, even in the
Case 1: Myocarditis absence of myocarditis (32). Electrophysiology consultation
Clinical presentation: A 65-year old man with advanced renal cell should be completed for consideration of insertion of cardiac
carcinoma presents with chest pain and dyspnea following 1 cycle device (pacemaker or defibrillator) if there is concern for ICI-
combination Ipilimumab/Nivolumab therapy. induced conduction disease. In the instance of cardiac device
Myocarditis is the most commonly documented cardiac insertion, the decision to proceed with ICI therapy should
irAE (27). Cardiovascular complications of ICIs are less well- be made in conjunction with the patient, cardiology, and
recognized, but these complications can be potentially fatal oncology. A surveillance strategy has recently been proposed that
(24, 28). The absolute incidence of cardiac irAE is reported at suggests a baseline cardiac assessment for all patients including
<1%, however the true incidence is likely higher given prior baseline cardiac risk factor assessment, electrocardiogram,
under-recognition of cardiac toxicity (26). Recently, Salem et al. cardiac troponin, and pro-brain natriuretic peptide (pBNP) in
reported that the odds of myocarditis in patients receiving ICIs addition to a non-invasive surveillance protocol for patients
was 11 times greater than patients who did not receive ICI with cardiac risk factors defined as pre-existing coronary artery
(24), with a median time of onset 30 days after initial exposure disease, hypertension, diabetes mellitus, obesity, smoking history,
to therapy. Wang et al. recently found that myocarditis has or positive family that should be completed within the initial
the highest fatality rate of any irAE (14). Manifestations of 12 weeks of therapy (32). Given the mortality risk of these
myocarditis are variable, with a clinical spectrum ranging from complications this approach may be appropriate, but should be
fatigue, chest pain, acute heart failure to cardiogenic shock, evaluated in prospective studies.
arrhythmias, and sudden death (29, 30). Pericarditis, conduction
disease and ventricular arrhythmias are other reported cardiac DERMATOLOGIC
irAEs, but acute myocardial ischemia, new onset systolic
dysfunction and Takotsubo syndrome can also occur (31). Case 1: Maculopapular Rash
Clinical presentation: A 61-year old woman with Merkel cell
Diagnostic Evaluation carcinoma presents with a pruritic rash after cycle two of
Myocarditis is characterized by elevated cardiac enzymes Avelumab therapy. She denies mouth pain, eye pain, fever, or
(troponin, pro-BNP), with/without the onset of left ventricular constitutional symptoms.
dysfunction and evidence of myocardial inflammation on Cutaneous toxicities are the most commonly encountered
cardiac MRI or PET/CT; all of these parameters should be irAE, and has been reported in 30–50% of patients receiving
investigated. In cases of uncertainty, endomyocardial biopsy can ICI therapy (33), with 37–70% of patients receiving CTLA-4 and
be useful although non-invasive investigations are preferred. 17–37% of patients receiving PD1/PDL-1 therapy experiencing
Initial evaluation of this patient was notable for marked dermatologic toxicities, respectively (2, 3). Of these, <3%
hypervolemia and pulmonary edema. Diagnostic workup was experience greater than grade 3 toxicity. Dermatologic irAEs
notable for non-specific ST-segment changes on ECG, marked are challenging as they have variable clinical presentation
elevation of cardiac markers and new reduced ejection fraction and timing of onset. Clinical manifestations range from
on transthoracic echocardiogram. Cardiac MRI was notable for pruritus, vitiligo, inflammatory rashes (maculopapular eruption,
late gadolinium enhancement overlying the basal left ventricular dermal hypersensitivity reactions, acneiform, exfoliative, and
lateral wall (see Figure 2B). psoriasiform lesions), bullous dermatoses (bullous pemphigoid,
bullous drug reaction) to severe cutaneous adverse reactions
Management (Stevens Johnson Syndrome, Toxic Epidermal Necrolysis,
The patient was transferred to the Cardiac Care Unit under Drug-induced hypersensitivity syndrome/Drug reaction with
the care of the cardiology team. ICI was permanently eosinophilia and systemic symptoms). Time to onset can
discontinued. The patient was monitored on continuous vary between 2 weeks and several months from onset of
telemetry and commenced treatment with daily intravenous 1 g therapy (34, 35).
methylprednisolone and diuretic therapy. His hospital course
was complicated by complete heart block that was managed with Diagnostic Evaluation
transvenous pacing, however, progressive clinical deterioration In patients with cutaneous irAE, a thorough clinical history
followed, resulting in cardiac arrest from which he could not and physical examination should be obtained. Clinicians
be resuscitated. should perform a close evaluation of all skin surfaces, mucus

membranes, and lymph nodes with a specific focus on Nephritis is the most common renal toxicity of anti-PD-1/PD-
the percentage body surface area that is involved and the L1 therapy, and is more common in patients with NSCLC treated
presence or absence of blistering. A positive Nikolsky sign with the combination of chemotherapy and immunotherapy,
(induction of blistering via mechanical pressure) should prompt which is now standard first-line therapy for patients with
concern for severe cutaneous reaction (SJS/TEN), which will advanced NSCLC (40). Hyponatremia may also be encountered
characteristically include mucosal and systemic involvement in these cases, however this occurs more commonly in the setting
(fever, constitutional symptoms). On examination, this patient of hypophysitis (41). There is significant heterogeneity in the
was noted to have tense blisters and erosions on her extremity onset of kidney injury; with CTLA-4 nephrotoxicity occurring
flexures that involved 15% body surface area. Nikolsky sign earlier (range: 2–3 months), compared to the later onset of injury
was positive. There was no evidence of ocular of mucosal with PD-1 related nephrotoxicity (range: 3–10 months) (42–
involvement. Hematological and biochemical investigations 44). Acute interstitial nephritis is the most prevalent pathologic
were normal. She was evaluated by a dermatologist and lesion, with one report of thrombotic microangiography (41).
underwent lesional and perilesional biopsies that confirmed the While initial data suggest that ICI-mediated renal injury ranged
diagnosis of bullous pemphigoid. Skin biopsy revealed linear from 1 to 2% in monotherapy and 4.5% in combination therapy
immunoglobulin G (IgG) and linear C3 staining along the (45), more recent studies have suggested a higher incidence
basement membrane zone, which is present in >90% of cases ranging from 9.9 to 29% (46).
(36). If biopsy is not possible, serum can be sent for antibodies to
BP180 and BP230 (ELISA testing) to confirm the diagnosis (36). Diagnostic Evaluation
Patients with renal irAEs are frequently asymptomatic and
Management therefore, routine monitoring of renal indices (serum
The patient was treated with betamethasone topical therapy and creatinine, electrolytes) is necessary to ensure prompt
oral prednisone 1 mg/kg, tapered over 4 weeks. The patient was detection. Symptomatic patients may present with nausea,
monitored closely with serial photography for progression but vomiting, fatigue, altered mental status, reduced urinary
displayed evidence of improvement. Avelumab was initially held, output, peripheral edema, or dyspnea. All patients should
but resumed upon resolution of symptoms to less than grade undergo complete renal evaluation including urinalysis,
1 severity. serum creatinine, serum electrolytes, and consideration for
With the exception of bullous disease, most grade 1 renal ultrasound to evaluate for other potential etiologies. In
and 2 cutaneous toxicities can be managed with topical this asymptomatic patient with Cr 2.5 mg/dl, urinalysis was
therapies (emollients, corticosteroids) and continuation of notable for pyuria with mild peripheral eosinophilia on CBC.
immunotherapy. Escalation of dermatologic care includes Investigations may reveal pyuria (68%), hematuria (16%),
holding immunotherapy, increasing the potency of topical and/or proteinuria on urinalysis with eosinophilia (21%) on
corticosteroids and starting systemic corticosteroids. Grade 4 CBC (41, 42).
toxicities should be treated with intravenous methylprednisolone
dosed at 1–2 mg/kg. Patients with >30% body surface area
Management
involvement should be managed in specialist burns unit. In
Therapy should be temporarily withheld while evaluation
steroid-refractory cases, IVIG or cyclosporine can be considered
for an underlying cause of nephrotoxicity is completed.
in conjunction with dermatology. Notably, cutaneous irAEs have
Should no alternate cause be identified, patients should
been recognized as a barrier to ICI compliance (11). Interestingly,
be presumed to have immune-mediated toxicity. Reflex
development of cutaneous toxicities may correlate with clinical
kidney biopsy is not recommended until corticosteroid
response in patients with metastatic melanoma, with a greater
treatment has been attempted. Corticosteroids are the mainstay
survival benefit reported in melanoma patients who developed
of treatment. Additional immunosuppression including
rash or vitiligo after pembrolizumab or nivolumab therapy,
mycophenolate can be considered in steroid-refractory cases. In
respectively (37, 38). Development of new vitiligo has also
this patient, Pembrolizumab was held temporarily. Nephrology
demonstrated a significant association with both progression-
were consulted and she was commenced on prednisone 1
free survival and overall survival in a meta-analysis of 27
mg/kg/day. At 2-week follow up Cr had improved to 1.8 mg/dl.
studies of melanoma patients treated with a wide variety of
Prednisone was tapered over 4 weeks with improvement
immunotherapeutic strategies (139 treatment arms comprising
in renal indices to baseline. Following discussion with
11 general immune stimulation, 84 vaccine, 28 antibody-based,
the patient regarding risks and benefits, pembrolizumab
and 16 adoptive transfer)(39).
was resumed.
RENAL
NEUROLOGY
Case 1: Nephritis
Clinical presentation: A 58-year old woman with stage IV Case 1: Encephalitis
PD-L1+ NSCLC was noted to have asymptomatic creatinine Clinical presentation: A 62-year old female with stage IV renal
(Cr) elevation to 2.5 mg/dl (baseline 0.9 mg/dl) after 2 cycles cell carcinoma presents with headache and altered mental status
of Pembrolizumab. 1 week following Ipilimumab/Nivolumab therapy.

Neurological toxicities, while uncommon, are of special Myasthenia gravis is estimated to occur in 0.1–0.2% of patients
interest due to their potential severity. These complications receiving immunotherapy (50, 51). Presentation is typically
encompass dysregulation of both central and peripheral within 2–3 weeks of treatment initiation (52, 53) with symptoms
nervous systems. Central manifestations include encephalitis, of fluctuating motor weakness and fatigue that is often associated
aseptic meningitis, transverse myelitis and posterior reversible with ocular and bulbar dysfunction. Peripheral neurotoxicity can
encephalopathy syndrome (PRES). Encephalitis is estimated also manifest as peripheral neuropathy, autonomic neuropathy,
to occur in 0.1–0.2% of patients (47). Patients may present Guillain-Barre syndrome, and necrotizing myositis.
with headache, altered mental status, motor or sensory deficits,
abnormal behaviors, personality change, speech disorders, or Diagnostic Evaluation
movement disorders. A meta-analysis of 9,208 patients who
Any concern for myasthenia gravis warrants rapid evaluation
received ICI therapy reported that incidence of neurologic
and intervention given the potential for respiratory compromise.
irAEs ranged from 3.8 to 6.1% with anti-CTLA4 and anti-PD-1
In this patient, acetylcholine receptor antibodies were positive.
monotherapy, respectively, and up to 12.0% with combination
Serial pulmonary function test with negative inspiratory force
therapy. High-grade events were reported at an incidence
(NIF) and vital capacity did not reveal respiratory compromise.
of <1% across all ICIs (47). The median time of onset to
Electrophysiologic testing (Single fiber EMG) confirmed the
encephalitis is 6 weeks. Most neurological irAEs present initially
diagnosis of myasthenia gravis. Other investigations including
with non-specific symptoms such as headache, dysgeusia and
creatinine kinase, aldolase, ESR, and CRP should be sent to assess
sensory impairment (47, 48).
for concurrent myositis. High clinical suspicion for concurrent
myositis and myocarditis is warranted given possibility of
Diagnostic Evaluation coexisting myasthenia gravis, myositis and myocarditis in a
A baseline complete blood count, liver, renal, and thyroid subset of patients as evidenced in 25% of cases of nivolumab-
function should be sent as well as assessment of the pituitary axis. related myasthenia gravis (52).
If there is concern for a vasculitic process, ESR, CRP, and ANCA
should be sent. Lumbar puncture should be completed to evaluate
for infection and leptomeningeal disease. Anti–N-methyl-D- Management
aspartate receptor (anti-NMDAR) antibody should also be sent. ICI-induced myasthenia gravis has been associated with a higher
Contrast-enhanced MRI brain scan and EEG monitoring can incidence of myasthenic crisis than idiopathic myasthenia gravis
be completed to assesses for vascular insult, brain metastasis (52, 53). Thus, a high level of suspicion and rapid initiation of
and subclinical seizure activity. In this patient, the diagnostic corticosteroids are mandatory to prevent clinical deterioration,
evaluation revealed an intact pituitary axis, with a subtle which can result in respiratory failure and death. In this patient,
hyperintensity of the right hippocampus on MRI (see Figure 2E). nivolumab therapy was held. Neurology were consulted and he
CSF analysis was notable for a lymphocytic pleocytosis with was commenced on pyridostigimine 30 mg four times per day
negative infectious, paraneoplastic and cytopathology panel. EEG as well as prednisone 1 mg/kg/day. With clinical improvement,
showed diffuse non-specific slowing. prednisone was slowly weaned in 5 mg decrements every 2 weeks.
Patients with grade 3 or 4 toxicity should be monitored in
the intensive care setting given risk of respiratory compromise.
Management
Pyridostigimine can be titrated to achieve optimal relief of
Prompt recognition and expeditious management carries the
symptoms. Additional therapeutic modalities include IVIG or
potential of complete neurological recovery (48, 49). In this
plasmapheresis that should be initiaited for grade 3 or 4 disease.
patient, ICI was held and she was commenced on IV acyclovir
that was discontinued on receipt of negative viral PCR
panel. Neurology were consulted. She was treated with pulse
corticosteroids (methylprednisolone 1 g IV daily for 5 days) as OCULAR
well as IVIG 2 g/kg over 5 days. Following 8 days of therapy with
corticosteroids and IVIG, she demonstrated full neurological Case 1: Uveitus
recovery. A recent case series of nine patients with ICI-induced Clinical Presentation: A 71-year old man with history of urothelial
neurological toxicity reported that 77.8% of patients showed cancer noted onset of right eye pain 5 weeks following cycle 1 of
marked symptomatic improvement following discontinuation of Atezolizumab therapy.
immunotherapy and management with corticosteroids (49). In Ophthalmic irAEs affect <1% of ICI-treated patients and
steroid-refectory cases, additional therapeutic modalities such as typically manifest as uveitis and/or dry eye (54, 55). Ocular
IVIG, rituximab or plasmapheresis can be considered, since this irAE have a median onset of 2 months and are more commonly
toxicity is autoantibody-mediated. associated with other concurrent irAEs (55). Patients can
present with eye pain, erythema, pain with eye movement,
visual disturbance, diplopia, or photophobia. Less commonly
Case 2: Myasthenia Gravis encountered ocular manifestations include inflammatory
Clinical Presentation: A 67-year old man with metastatic colorectal orbitopathy, keratitis, choroidal neovascularization, serous
cancer presents with diplopia 1 week following the first cycle of retinal detachment, retinopathy, neuroretinitis, and ocular
Nivolumab therapy. myasthenia gravis.

Diagnostic Evaluation Diagnostic Evaluation

Ocular irAEs are commonly seen in associated with other The patient underwent thorough history and physical
systemic irAEs, therefore clinical suspicion for other examination that was notable only for hypoxia with O2
manifestations should be high. This particular patient endorsed saturation of 88% on room air. Physical examination in
the presence of visual floaters, but denied pain with eye CIP can be very unrevealing and thus clinicians must be
movement, change in color perception, visual change, or vigilant for early detection. The differential diagnosis should
photophobia. On examination, the patient’s right pupil was include respiratory infection, rare respiratory infections such
mildly constricted, reactive to light with erythema of the limbus. as PCP or aspergillosis (especially if being treated with high-
Left pupil was round and reactive. Color vision and visual acuity dose corticosteroids), tumor progression, radiation-induced
were intact. Red reflex was present bilaterally. There was no pneumonitis, and ICI-induced myocarditis/cardiac failure.
evidence of concurrent irAE. Further diagnostic evaluation should include infectious
evaluation (urine, respiratory culture, viral culture/swab, blood
Management cultures, serum galactomannan), CT imaging and consideration
The patient was prescribed topical corticosteroid, 1% for bronchoscopy with bronchoalveolar lavage (BAL) +/– lung
cyclopentolate (topical cyclopegic agent) and prednisone biopsy. This patient underwent CT imaging with findings as
60 mg daily. An urgent ophthalmology appointment was illustrated in Figure 2F. Infectious evaluation was negative for
scheduled within a week. Atezolizumab was temporarily held the presence of an infectious organism. Bronchoscopy with
until completion of corticosteroid taper over 2 months. BAL was notable for the presence of chronic lymphocytes
The majority of ocular irAE do not necessitate discontinuation and macrophages with type-II pneumocyte hyperplasia. High-
of ICI and are managed with topical therapies. All patients resolution CT chest is the imaging modality of choice, with
should be referred to ophthalmology for slit-lamp and dilated common manifestations including ground-glass opacities or
fundus examination to assess for presence of leukocytes in the patchy nodular infiltrates, predominantly in the lower lobes
anterior chamber of the eye as well as to examine the extent (60). This should ideally be done with contrast, to rule out
of inflammation. In this case, ICI was temporarily held in the the presence of a pulmonary embolus. Five distinct types
setting of grade 2 toxicity. However, ICI should be permanently of radiologic abnormalities of CIP have been described,
discontinued with emergent ophthalmology assessment in including cryptogenic organizing pneumonia (COP) like ground
higher grade irAEs. Additional therapeutic strategies include glass opacities, interstitial, hypersensitivity, and pneumonitis
systemic and topical/intravitreal corticosteroids. Infliximab can not-otherwise-specified (61).
be considered in steroid refractory cases (56).
Management
PULMONARY Corticosteroid therapy is the mainstay of CIP management, with
>80% of CIP patients having their pneumonitis improve or
Case 1: Pneumonitis resolve with corticosteroids alone. Pulmonology assessment is
Clinical presentation: A 54-year-old man with advanced urothelial often warranted in any patient with suspected CIP, to evaluate
carcinoma presents following the fifth dose of Durvalumab for bronchoscopy or help to rule out alternative etiologies. In
with dyspnea. this patient with grade 2 CIP, ICI was temporarily held while
Checkpoint-inhibitor pneumonitis (CIP) is defined as the the patient was treated with prednisone 1 mg/kg/d, followed
development of new infiltrates on chest imaging with dyspnea by 5 mg/week taper over 4 weeks. Interval CT imaging at 4
or other respiratory symptoms in the absence of infection, weeks was notable for improvement in radiographic findings.
cardiac dysfunction or tumor progression. Presentations can In this case, since CIP resolved, the patient’s ICI-therapy was
be heterogeneous, ranging from asymptomatic radiographic restarted. While grade 1 or 2 CIP can be managed with low-dose
findings, chest pain, cough, or dyspnea, to life-threatening corticosteroids and close observation, higher-grade CIP should
respiratory compromise (57). The overall incidence of CIP ranges be treated with high-dose corticosteroids (methylprednisolone
from 0 to 10%, with a median time to onset of ∼3 months IV 1–2 mg/kg/d). Infectious disease should be consulted in
reported by Naidoo et al. (8). Patients receiving combination ICI addition to the pulmonary team to rule out common or unusual
therapy are at increased risk of CIP (10 vs. 3%, respectively; p infections, and in some cases, empiric antimicrobials may be
< 0.001), with evidence to suggest that these patients experience given when infection cannot be completely excluded. Lung
symptoms earlier in the clinical course (8, 57). In a study biopsies are typically not warranted, but may be useful rule
of fatal ICI-associated toxic effects, anti–PD-1/PD-L1–related out infection or lymphangitic tumor spread. Patients that do
fatalities were often from pneumonitis, consisting of 35% of all not demonstrate clinical improvement in CIP within 48–72 h
fatalities (14). The data would suggest that higher grade CIP should be considered for second-line therapies, options include
tend to occur within the first 100–200 days of therapy initiation infliximab, mycophenolate mofetil, IVIG, or cyclophosphamide.
(57). Emerging data from the Johns Hopkins Hospital group Retrospective studies have noted that up to 86% of CIP improves
has shown that tumor histology may be a risk factor for CIP with corticosteroid treatment, however, of concern there was
in NSCLC patients (58). Furthermore, multistate modeling has very poor response to additional immunosuppression (8, 62).
demonstrated that NSCLC patients who develop CIP may have a In addition, a recent retrospective analysis has found that
poorer survival (59). pneumonitis is associated with worse survival (63). There is

currently a deficit in evidence for salvage treatment in steroid events are unique as the manifestations are often irreversible and
refractory patients. This is an area under current development patients often require lifelong hormone replacement (66).
to ameliorate the morbidity and mortality associated with
respiratory-induced adverse events. Case 2: Hypothyroidism
Clinical presentation: A 60 year old female patient with stage-
III lung adenocarcinoma treated with durvalumab, has a thyroid
ENDOCRINE
stimulating hormone (TSH) of 8.5 mIU/l with normal free
Case 1: Hypophysitis thyroxine (fT4). She was asymptomatic.
Clinical presentation: A 70-year old male with advanced renal Hypothyroidism is one of the most common irAEs from
cell carcinoma receiving Ipilimumab/Nivolumab, presents with anti-PD-1, anti-PD-L1, and anti-CTLA-4 ICIs. A systematic
new-onset fatigue and dizziness after 2 cycles of therapy. review and meta-analysis by Barroso-Sousa et al. demonstrated
Immune-related endocrine events pose a clinical challenge that the overall incidence of hypothyroidism was 6.6% (65).
as symptoms are often subtle. Patients can present with Hypothyroidism can present with fatigue, unintentional weight
non-specific symptoms including nausea, vomiting, dizziness, gain, cold intolerance, constipation, myalgia, and dry skin.
headache, fatigue, and malaise. The pituitary, thyroid, pancreas,
and adrenal glands are the organs most commonly affected, Diagnostic Evaluation
although parathyroid involvement has also been reported Physical examination may be notable for goiter, bradycardia,
(64). The incidence of immune-related endocrinopathies was diastolic hypertension, or delayed deep tendon reflexes. TSH
approximately 10% in a recent meta-analysis of 7,551 patients and fT4 should be completed prior to initiation of ICI therapy
that received ICI (63). The risk of endocrine irAE is greatest and should be monitored every 4–6 weeks. It is important
with combination therapy, with rates of hypothyroidism (17%), to differentiate primary from secondary hypothyroidism as
hypophysitis (13%), and hyperthyroidism (10%) reported (4, 65). discussed above, as well as differentiate hypothyroidism from
late-phase thyroiditis. Elevated TSH with low fT4 is indicative
Diagnostic Evaluation of biochemical hypothyroidism. Upon detection, thyroid
In this particular patient, a physical examination was notable peroxidase (TPO) antibody should also be sent.
for intact visual fields, however, laboratory assessment showed
mild hyponatremia, with both low TSH and free T4. Morning Management
ACTH and cortisol were also low. MRI brain was notable for Durvalumab therapy was continued. At 4 week follow-up, TSH
pituitary enhancement. level was noted to be elevated to 12 mIU/ml with normal fT4.
In patients with suspected hypophysitis, the pituitary- She remained asymptomatic. However, given TSH >10 mIU/l,
hypothalamic axis should be examined including free T4, she was commenced on 75 mcg of levothyroxine daily. In patients
TSH, LH, FSH, ACTH, and cortisol, as well as serum with grade 1 hypothyroidism, ICIs may be continued with close
electrolytes. It is imperative to discern between primary vs. monitoring of TSH and fT4. For grade 2 toxicity, appropriate
secondary hormonal deficiencies, as this will guide appropriate thyroid supplementation should be administered with either
management. Clinicians should recognize that hypophysitis can continued ICIs or temporary withholding until symptomatic
result in secondary adrenal insufficiency and hypothyroidism. patients with any level of TSH elevation or in asymptomatic
Failure to recognize this disease entity can have negative patients with TSH levels that persist >10 mIU/l (measured
consequences for patient care; replacing thyroid hormone prior 4 weeks apart) improve. Grade 3 and 4 toxicities should be
to cortisol repletion can precipitate adrenal crisis. treated as grade 2 unless signs of myxedema (decreased mental
status, hypotension, hypoglycemia, bradycardia, hypothermia)
Management are present, in which case hospitalization for supportive therapy
Ipilimumab/Nivolumab therapy was temporarily held. In may be recommended. In general, TSH should be monitored
consultation with endocrinology, the patient was started on every 6–8 weeks while titrating hormone replacement until a
hydrocortisone 10 /5 mg in morning and afternoon, respectively. normal TSH is reached, with repeat testing annually or as
One week later he was started on a weight-based dose of clinically indicated.
levothyroxine. The patient was provided with “sick day”
instructions for stress dosing of hydrocortisone and a medical HEMATOLOGY
alert bracelet. The patient demonstrated clinical improvement
and was restarted on PD-1 monotherapy. Case 1: Thrombocytopenia
It is recommended that ICI is held for any-grade hypophysitis. Clinical presentation: A 50-year old female with PD-L1+
Once patients demonstrate stability on hormonal replacement, metastatic lung adenocarcinoma presents with petechiae after 3
ICI can be restarted. Higher-grade hypophysitis (grade 3+) can cycles of pembrolizumab treatment.
be managed with an initial pulsed dose of corticosteroids. Free Hematologic irAE that may occur from anti-PD-1/PD-
T4 should be monitored for levothyroxine replacement. Key L1/CTLA-4 include autoimmune hemolytic anemia, acquired
concepts of management include high index of clinical suspicion, thrombotic thrombocytopenia, hemolytic uremic syndrome,
appropriate localization of endocrine dysfunction, replacement immune mediated thrombocytopenia, lymphopenia, and
of hormones and close monitoring. Immune-related endocrine acquired hemophilia. Thrombocytopenia due to ICI is

relatively infrequent, with reports ranging from 1 to 28% was 0.58 and 0.16, respectively (73). Combination PD-1/CTLA-
of patients (67–69). 4 related deaths were recently found to be most frequently
from colitis, accounting for 37% of fatalities (14). The time
Diagnostic Evaluation of onset is typically 5–10 weeks following initiation of therapy
In patients who develop thrombocytopenia during ICI therapy, (74). ICI-induced hepatotoxicity has also been well-described,
other etiologies for this presentation should be considered, with incidence of 2–10% of patients receiving monotherapy (75)
including bone marrow suppression, infiltration, platelet and 25–30% of patients being treated with combination PD-
destruction, or platelet sequestration, with a differential 1/CTLA-4 therapy (75). Hepatitis has been found to be the
diagnosis of myelodysplastic syndrome, disseminated second most common irAE leading to fatal outcomes anti–PD-
intravascular coagulation, ICI-mediated thrombocytopenia, 1/PD-L1 therapy (14). The time of onset of hepatitis may also
acquired thrombotic thrombocytopenia (TTP), and hemolytic occur early in a patient’s treatment course; typically commencing
uremic syndrome (HUS). A thorough history is important within the first 6–12 weeks after treatment initiation (76). Other
to evaluate for drug/toxin exposures or viral infections that less frequently reported GI toxicities include dysphagia, gastritis,
may have led to thrombocytopenia. In this patient, CBC was duodenitis, and pancreatitis (77).
notable for normal hemoglobin with grade 2 thrombocytopenia
(platelets 70,000/µl). Renal function was normal. There Diagnostic Evaluation
was no evidence of platelet consumption or hemolysis on a Diagnostic work-up for colitis includes standard laboratory
peripheral blood smear. Hemolysis labs including serum lactate testing to assess for infectious vs. non-infectious etiologies
dehydrogenase (LDH), haptoglobin, indirect bilirubin, and including CBC, CMP, ESR, and CRP. Stool cultures (bacterial,
CBC were normal. HIV, hepatitis B/C virus and H. pylori were viral, ova, and parasites) should be obtained as well as
negative. Thus, ICI-mediated immune thrombocytopenia was stool calprotectin or lactoferrin to monitor disease activity,
the most likely diagnosis. extrapolated from the management of inflammatory bowel
disease. In patients with severe colitis, tuberculosis testing should
Management be completed in potential preparation for the use of anti-TNF-
In this patient, ICI was held for 2 weeks, and a repeat CBC α inhibitors for steroid-refractory colitis. Patients should also
did not show improvement in platelet count until prednisone undergo radiologic imaging with a CT abdomen, which may
1 mg/kg/dose was started. Re-evaluation at 2 weeks revealed show mesenteric vessel engorgement, colonic wall thickening,
improvement to grade 1 thrombocytopenia (Platelets 90,000/µl). colonic distension, and pericolonic fat stranding (76). In severe
Prednisone was tapered over 4 weeks, and the patient was able to cases, in those in which the diagnosis is uncertain, and to
be recommenced on pembrolizumab. evaluate the severity of colitis, direct visualization of the colon
Most patients with low-grade thrombocytopenia improve with either a colonoscopy or flexible sigmoidoscopy should be
with ICI withholding and initiation of oral corticosteroids. considered. The presence of ulceration on direct visualization
For higher-grade toxicities, a hematology service should be is associated with a corticosteroid-refractory course, and early
consulted for consideration of additional therapies for severe infliximab can be considered in these cases. ICI-induced colitis
toxicity, such as IVIG, rituximab, cyclosporine A, mycophenolate has been reported to have greater predilection for descending
mofetil, cyclophosphamide, or thrombopoietin receptor agonists. colon (see Figure 2G) (71, 76). Endoscopy is also useful in
If indicated, IVIG initial dosing is recommended at 1 g/kg as a monitoring colitis, particularly when resumption of therapy is
one-time dose which can be repeated if necessary (70). being planned.
This patient underwent extensive evaluation as delineated
above. CT imaging revealed thickening of descending colon with
GASTROINTESTINAL pericolonic fat stranding. Gastroenterology were consulted who
completed colonoscopy, which demonstrated diffuse ulceration
Case 1: Colitis at the descending colon.
Clinical presentation: A 45-year old male with advanced
melanoma presents to the ED with abdominal pain, non-bloody Management
diarrhea (>7 bowel movements per day) and fever 2 days after The patient was managed with intravenous fluids and prednisone
receiving 3rd dose of combination Ipilimumab/Nivolumab therapy. 1 mg/kg/day. This resulted in clinical improvement, with
The most common GI toxicities reported from anti-CTLA-4 reduction in bowel movement to three times per day. The patient
ICIs are diarrhea and colitis. Colitis is defined as inflammation of was continued on the initial corticosteroid dose for a further
the lining of the colon, as opposed to diarrhea that is defined as 4 days, and then steroids were tapered over 4 weeks. Upon
increased number of bowel movements. completion of the prednisone taper, nivolumab monotherapy
The incidence of colitis ranges from 8 to 27% with rates was resumed.
of diarrhea reported up to 54% of CTLA-4 treated patients. Patients with grade 2+ colitis should have ICI withheld,
The incidence is greatest in patients treated with CTLA-4 and treatment should only be resumed if toxicity improves to
monotherapy vs. CTLA-4/PD-1 combination therapy (71, 72). <grade 1. Cases of grade 3+ colitis often imply permanent
When PD-1 inhibitors were compared directly with CTLA- discontinuation of anti-CTLA-4 therapy (74). Early intervention
4 inhibitors, the relative risk of all-grade diarrhea and colitis with corticosteroids and best supportive care with hydration,

electrolyte repletion and antidiarrheal agents is crucial. If patients combination therapies (4, 5, 65). Patients with pre-exiting
do not demonstrate adequate clinical response within 48–72 h autoimmune disease appear to be at increased risk of irAE.
of corticosteroid therapy, TNF-blocker therapy with infliximab A number of retrospective studies have indicated that while
should be commenced. This can be repeated again at a 2-week patients with pre-existing may be at increased risk for both
interval. Vedolizumab, an anti-integrin α4β7 antibody, should be exacerbation of their autoimmune condition and for de novo
considered in patients who develop colitis that is refractory to immune-related adverse, this should not preclude treatment (95).
infliximab or in cases that anti-TNF- α therapy is contraindicated. Studies regarding other risk factors for developing irAE are
lacking. There is likely a genetic predisposition to irAE given the
DISCUSSION role of genetics in autoimmune disease, indeed, in PD-1 deficient
mice, genetic backgrounds were found to have different degree
Currently, there is a paucity of literature on the precise and divergent autoimmune conditions (79, 96, 97). Cappelli
immunopathogenesis of specific irAEs, however several et al. recently evaluated immunogenetics in patients with ICI-
mechanisms have been suggested that vary depending on the induced IA and found that patients of European descent were
irAE in question. more likely to be positive for HLA-DRB1 shared epitope alleles
A mechanism for irAE development due to enhanced T than population controls (98). Furthermore, patients with CTLA-
cell activity against shared antigens across normal and cancer 4 gene variant 1661A>G may predispose melanoma patients
cells is supported by several preclinical models in autoimmune to the development of endocrine irAEs (99). In addition, the
myocarditis and autoimmune dilated cardiomyopathy (78, 79). JHH group have recently demonstrated that in NSCLC, tumor
In addition, abrogation of PD-1 pathway may contribute to histologic type may be a risk factor for CIP development and that
the pathogenesis of rheumatoid arthritis and giant cell arteritis the development of CIP worsens survival in patients receiving
(80, 81). Furthermore, vitiligo is the most common cutaneous immunotherapy (58, 59).
irAE in patients with melanoma, likely as a consequence of shared A new wave of research is focused on identification
antigens on melanoma cells and melanocytes (82). Elevated of irAE biomarkers, which would enable identification of
levels of inflammatory cytokines are also likely involved in the populations at higher risk for development of irAE. Both
pathophysiology of irAE. Both PD-1 and CTLA-4 therapies obesity and smoking result in pro-inflammatory state (100–
have been found to promote Th1- and Th17-mediated immune 102). An “inflamed phenotype” may exist that could affect
responses resulting in elevated circulating levels of IL-17 and both therapeutic responses and toxicity risk. It may also be of
IFN-γ (83–85). Insights into the pathogenesis of ipilimumab- benefit to account for the baseline inflammatory profiles present
induced enterocolitis has facilitated the use of steroid-sparing in the patient prior to ICI, but this is an area that requires
agents such as infliximab and vedolizumab in this particular additional research. The risk of both therapeutic and adverse
irAE (86, 87). Another potential mechanism is that of increased effects of ICI may also be modulated by the gut microbiota
levels of pre-existing autoantibodies seen with ICI-induced (103). Preclinical studies have found that Bifidobacteria promote
myasthenia gravis, autoimmune hemolytic anemia, autoimmune the natural antitumor immune responses, possibly by inducing
thyroiditis and type 1 diabetes mellitus (88–92). Finally, CTLA- a favorable shift toward Th1 responses (104). Patients treated
4 therapy has been found to cause hypophysitis, likely due with CTLA-4 therapy with a predominance of bacteria from
to enhanced complement-mediated inflammation due to direct the Bacteroidetes phylum were found to have reduced rates
binding of anti-CTLA-4 antibody with CTLA-4 expressed on of ipilimumab-induced colitis (105). These findings raise the
normal pituitary tissue (93). Further insights would allow the possibility that variations in gastrointestinal flora that affect
development of personalized and targeted therapies for patients, host immunity influence the risk of irAE. Indeed, differences
potentially reducing exposure to prolonged immunosuppression, in the intestinal microflora of patients may explain some of the
thereby enhancing efficacy and reducing toxicity of treatment. heterogeneity in immunotherapeutic and toxicity outcomes in
The association of irAE with efficacy of ICI therapy is also patients receiving ICI therapy. A number of therapeutic avenues
under investigation. As detailed previously, development of are currently being explored. Anderson and Rapport recently
vitiligo has demonstrated a significant association with beneficial suggested a biomarker profile incorporating IL-17/IFN-γ/IL-
clinical outcomes (39). A recent multicenter retrospective study 10/TGF-β1/CRP based on findings from ipilimumab-associated
of patients with advanced NSCLC treated with nivolumab colitis (106). Other potential biomarkers include measurement of
monotherapy found that the development of irAEs was a circulating neutrophil activation using myeloperoxidase/matrix
strong predictor of survival outcomes (94). Indeed, patients metalloproteinase 9/L-selectin (107).
who experienced two or more irAEs had a more pronounced
survival benefit, suggesting a mechanistic association between CONCLUSION
irAEs and immunotherapy efficacy. These findings have not
been universally confirmed, but certainly raises the question Immunotherapy is associated with a unique side effect profile
of whether the degree of immune activation is associated with that can result in significant morbidity and mortality. Immune-
superior treatment effect. related toxicities require prompt recognition and intervention to
Risk factors for the development of irAEs are also being optimize clinical outcomes. As immunotherapy enters common
evaluated. The clinical manifestations, timing, and severity clinical practice, it is crucial that multidisciplinary collaborations
of irAE appear to depend on immunotherapy regimen, are established to improve the recognition and management of
with increased frequency and severity demonstrated with common or serious irAE, in particular. In this emerging field,

an anti-cancer therapy that is able to selectively kill cancer AUTHOR CONTRIBUTIONS

cells without causing toxicities to normal cells, remains elusive.
Further research is required to enhance our understanding and This review was drafted by CC and KB and critically revised
to define the immunopathogenesis of irAE so that strategies by JN.
for prevention, early detection and targeted therapy can
be developed. ACKNOWLEDGMENTS
CONSENT We would like to acknowledge the contributions of
members of the JHH irAE Toxicology Board who provided
Written and informed institutional consent was provided for the clinical images including Dr. Tawnie Braaten, Dr. Laura
use of clinical images. The clinical cases presented in this review Cappelli, Dr. Roberta Florido, Dr. Shawn Kwatra, and
are fictional. Dr. John Probasco.
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published: 20 June 2019

Immune-Related Adverse Events: A

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TABLE 2 | Common terminology criteria for adverse events grading.

CTCAE grade Level of care Management ICI therapy

1: Asymptomatic or Mild Ambulatory Observation Continue ICI therapy with close

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Diagnostic Evaluation Diagnostic Evaluation

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an anti-cancer therapy that is able to selectively kill cancer AUTHOR CONTRIBUTIONS

REFERENCES 15. Santini F, Rizvi H, Plodkowski A, Ni A, Lacouture M, Gambarin-

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