Immune-Related Adverse Event (irAE) Management Tool

Immune-related adverse events or irAEs (also known as immune-mediated adverse events or imAEs) are specific AEs caused by immunotherapy. Intervention and management is critical for the management as irAEs can develop at any point during a patient’s course of therapy, even after the end of therapy.

Please select the AEs below that have been identified with the patient to understand the best methods for management and safety.

*Please note that this is not an exhaustive list of irAEs however, and are select AEs that are manageable.

1. Jin, K. T. et al. Immune-mediated adverse effects of immune-checkpoint inhibitors and their management in cancer. Immunol. Lett. 221, 61–71 (2020).
2. Daniels GA, Guerrera AD, Katz D, Viets-Upchurch J. Challenge of immune-mediated adverse reactions in the emergency department. Emerg Med J. 2019;36(6):369-377
3. “National Comprehensive Cancer Network – Management of Immunotherapy-Related Toxicities .” Version 1.2022 – February 28, 2022 https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf.

Click on the checkboxes below to select proper irAEs accounted for, then click NEXT to proceed:
*Check All that Apply*
[hover for additional information on presentation of symptoms]

For all irAEs remember the key steps of Look, Listen, and Recognize

Please consider these questions with your patient when determining signs and symptoms:

Steps:

Please view the Grading table below (CTCAE 5.0) for each irAE tab confirmed and CLICK on the corresponding grade for proper management techniques. Guideline recommendations on dose modifications, interruptions, or discontinuations should be determined in accordance with the applicable product label and the clinical judgement of the treating HCP
When you have found the proper grade, click SAVE underneath the Grade level management. You must save exactly 1 grade on each tab
When finished saving all associated management on each irAE Tab, click FINISH at the bottom of the page to print out the report notes
If you would like to add/remove/or change irAEs, click GO BACK

Hypophysitis clinical symptoms: headache, dizziness, nausea/emesis, anorexia, and/or severe fatigue, low blood pressure, lethargy, confusion

Hypophysitis lab abnormalities: low ACTH, low cortisol, sometimes low serum sodium or abnormalities of other pituitary hormones

Managing the IO regimen:	Hold IO therapy until acute symptoms resolve and hormone replacement initiated
irAE management:	Obtain a morning cortisol and ACTH, TSH, free T4, LH, FSH, testosterone (males), estrogen (premenopausal females) If symptomatic: brain MRI +/- contrast with pituitary/sellar cuts Endocrine consultation If acute symptoms persist with concern for mass effect: carefully consider high-dose steroids Initiate hormone replacement therapy as indicated: Secondary adrenal insufficiency (low ACTH, low cortisol): steroid replacement Central hypothyroidism (low TSH, low FT4): thyroid replacement, follow free T4 level for dose titrations
SAVE

Potential symptoms to watch: changes from scratching (e.g. edema, papulation, excoriations, lichenification, oozing/crusts), characterized by inflammation of the skin and presence of bullae, which are filled with fluid; SCARs are characterized by separation of epidermis from dermis

CTCAE 5.0

Grade Severity	1	2	3	4
Bullous dermatitis	Asymptomatic Blisters covering < 10% BSA	Blisters covering 10-30% BSA Painful blisters Limiting instrumental ADLs	Blisters covering > 30% BSA Limiting self-care ADLs	Blisters covering > 30% BSA Associated with fluid or electrolyte abnormalities ICU care or burn unit indicated
Steven-Johnson Syndrome (SJS)			Skin sloughing covering < 10% BSA with associated signs (e.g. erythema, purpura, epidermal detachment, and mucous membrane detachment)	Skin sloughing covering 10-30% BSA with associated signs (e.g. erythema, purpura, epidermal detachment, and mucous membrane detachment)
Toxic Epidermal Necrolysis (TEN)				Skin sloughing covering >/= 30% BSA with associated signs

Managing the IO regimen:	Consider holding IO therapy
irAE management:	Treatment with high-potency topical corticosteroids to affected areas
SAVE

Managing the IO regimen:	Hold IO therapy until < Grade 1
irAE management:	Prednisone/methylprednisolone 0.5-1 mg/kg/day until symptoms improve to ≤ Grade 1, then taper over 4-6 weeks If no improvement after 3 days: consider adding rituximab
SAVE

Managing the IO regimen:	Discontinue IO therapy
irAE management:	Requires hospitalization Urgent dermatology consultation Prednisone/methylprednisolone 1-2 mg/kg/day If no improvement after 3 days: consider adding rituximab Consider IVIG 1 g/kg/day x 2 days with monthly cycles until clear as adjunct to rituximab
SAVE

Managing the IO regimen:	Permanently discontinue IO therapy
irAE management:	Requires hospitalization Urgent dermatology, ophthalmology, and urology consultations Prednisone/methylprednisolone 1-2 mg/kg/day Consider IVIG 1 g/kg/day in divided doses x 3-4 days Consider other immunosuppressive therapies such as etanercept and cyclosporine
SAVE

Colitis symptoms: watery diarrhea, cramping, urgency abdominal pain, blood and mucus in the tool, fever, nocturnal bowel movements; blood in stool and/or fever should prompt a more throughout workup for infection and other causes of GI bleed

CTCAE 5.0

Grade Severity	1	2	3	4
Diarrhea	Increase of < 4 stools per day over baseline Mild increase in ostomy output compared to baseline	Increase of 4-6 stools per day over baseline Moderate increase in ostomy output compared with baseline Limiting instrumental ADL	Increase of ≥7 stools per day over baseline Hospitalization indicated Severe increase in ostomy output compared with baseline Limiting self-care ADL	Life threatening consequences (eg, hemodynamic collapse, ischemia, bleeding, perforation, toxic megacolon) Urgent intervention indicated
Colitis	Asymptomatic Clinical or diagnostic observation only Intervention not indicated	Abdominal pain Blood or mucus in stool	Severe abdominal pain Peritoneal signs	Life threatening consequences (eg, hemodynamic collapse, ischemia, bleeding, perforation, toxic megacolon) Urgent intervention indicated

Managing the IO regimen:	Consider holding IO therapy
irAE management:	Hydration Dietary modifications Consider stool evaluation to rule out infectious etiology Consider loperamide or diphenoxylate/atropine for 2-3 days as adjunct for symptom relief If symptoms persist or progress: check lactoferrin/calprotectin If positive: treat as Grade 2 If negative and no infection: continue Grade 1 management and consider adding mesalamine and/or cholestyramine as needed
SAVE

Managing the IO regimen:	Hold IO therapy
irAE management:	Stool evaluation to rule out infectious etiology Consider fecal lactoferrin/calprotectin Consider GI consultation Consider abdominal/pelvic CT with contrast For pathologically-confirmed microscopic colitis: consider budesonide 8 mg daily prior to steroids Prednisone/methylprednisolone 1-2 mg/kg/day If no response after 2-3 days: continue steroids and consider adding infliximab or vedolizumab within 2 weeks Duration not clearly defined but evidence supports up to three doses at weeks 0, 2, and 6 is associated with reduced recurrence rates Consider tofacitinib or ustekinumab for infliximab- and/or vedolizumab-refractory colitis
SAVE

Managing the IO regimen:	Anti-CTLA-4: discontinue Anti-PD-1/PD-L1: hold and consider resuming after resolution of toxicity Grade 4: permanently discontinue IO agent responsible for toxicity
irAE management:	Consider hospitalization Initiate methylprednisolone 1-2 mg/kg/day If no response in 2-3 days: continue steroids and strongly consider adding infliximab or vedolizumab Duration not clearly defined but evidence supports up to three doses at weeks 0, 2, and 6 is associated with reduced recurrence rates Consider tofacitinib or ustekinumab for infliximab- and/or vedolizumab-refractory colitis
SAVE

Potential symptoms to watch: characterized by presence of macules (flat) and papules (elevated), frequently affect the upper trunk spreading centripetally, may be associated with pruritis

CTCAE 5.0

Grade Severity	1	2	3
Rash maculo-papular	Macules/papules covering < 10% BSA with or without symptoms (eg. pruritis, burning, tightness)	Macules/papules covering 10-30% BSA with or without symptoms (eg. pruritis, burning, tightness) Limiting instrumental ADL Rash covering >30% BSA with or without mild symptoms	Macules/papules covering >30% BSA with moderate or severe symptoms Limiting self-care ADL

Managing the IO regimen:	Continue IO therapy
irAE management:	Topical emollient Oral antihistamine for pruritis Treatment with moderate-potency topical corticosteroids to affected areas
SAVE

Managing the IO regimen:	Continue IO therapy
irAE management:	Topical emollient Oral antihistamine Treatment with high-potency topical steroids to affected areas If unresponsive to topical steroids within 1 week: consider prednisone 0.5 mg/kg/day
SAVE

Managing the IO regimen:	Hold IO therapy
irAE management:	Consider hospitalization Treatment with high-potency topical steroids to affected areas Prednisone 0.5-1 mg/kg/day (increase up to 2 mg/kg/day, if no improvement
SAVE

Clinical Signs: Oxygen saturation (resting and with ambulation), PFT for high-risk patients, consider chest CT

CTCAE 5.0

Grade Severity	1	2	3	4
Pneumonitis	Asymptomatic Clinical or diagnostic observations only Intervention not indicated	Symptomatic Medical intervention indicated Limiting instrumental ADLs	Severe symptoms Limiting self-care ADL Oxygen indicated	Life threatening respiratory compromise Urgent intervention indicated (e.g., tracheotomy or intubation)

NCCN Grading Scale

Grade Severity	1	2	3	4
Pneumonitis	Asymptomatic Confined to one lobe of the lung or < 25% of lung parenchyma	Presence of new/worsening symptoms Consider cardiac etiologies	Involve all lung lobes or > 50% of lung parenchyma Limiting self-care ADLs Oxygen indicated	Life-threatening respiratory compromise

Managing the IO regimen:	Consider holding IO therapy and re-assess in 1-2 weeks
irAE management:	Consider chest CT with contrast Consider repeat chest CT in 4-6 weeks or as clinical indicated if symptoms develop
SAVE

Managing the IO regimen:	Hold IO therapy If imaging abnormalities resolve and no requirement for steroid, consider resuming
irAE management:	Consider pulmonary consultation, infectious workup, and chest CT with contrast (with repeat chest CT in 3-4 weeks) Consider bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy if clinically indicated Consider empiric antibiotics with coverage for atypical pathogens if infection not fully excluded Initiate prednisone/methylprednisolone 1-2 mg/kg/day Monitor every 3-7 days with H&P and pulse oximetry (resting and with ambulation) If no improvement after 2-3 days of corticosteroid, treat as Grade 3
SAVE

Managing the IO regimen:	Permanently discontinue IO therapy
irAE management:	Hospitalize Pulmonary and infectious disease consultation with infectious workup Consider bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy if clinically indicated Consider empiric antibiotics with coverage for atypical pathogens if infection not fully excluded Initiate methylprednisolone 1-2 mg/kg/day Assess response within 48 hours and plan taer over >/= 6 weeks If no improvement after 2 days: consider infliximab 5 mg/kg A second dose may be repeated 14 days later at discretion of provider Other options: IVIG, mycophenolate 1-1.5 g BID then taper
SAVE

Potential symptoms to watch: Occurs either alone or associated with maculopapular rash

Clinical Signs: Characterized by an intense itching sensation

CTCAE 5.0

Grade Severity	1	2	3
Pruritis	Mild or localized Topical intervention indicated	Widespread and intermittent Skin changes from scratching (e.g. edema, papulation, excoriations, lichenification, oozing/crusts) Oral intervention indicated Limiting instrumental ADLs	Widespread and constant Limiting self-care ADLs or sleep Systemic steroids or immunosuppressive therapy indicated

Managing the IO regimen:	Continue IO therapy
irAE management:	Oral antihistamine Localized pruritis: treatment with moderate-potency topical corticosteroid to affect areas
SAVE

Managing the IO regimen:	Continue IO therapy with intensified antipruritic therapy Consider holding IO therapy in select cases
irAE management:	Dermatology consultation Oral antihistamines Consider gabapentinoids (gabapentin or pregabalin) Treatment with high-potency topical corticosteroids to affects areas Refractory cases: consider narrow-band UVB phototherapy
SAVE

Managing the IO regimen:	Hold IO therapy
irAE management:	Urgent dermatology consultation Oral antihistamines Prednisone/methylprednisolone 0.5-1mg/kg/day until symptoms improve to ≤ Grade 1 then taper over 4-6 weeks Consider gabapentinoids (gabapentin or pregabalin) Refractory cases: consider aprepitant, dupilumab, omalizumab, or narrow-band UVB phototherapy
SAVE

Potential symptoms to watch: Identifying immune-mediated renal toxicity is mainly one of exclusion

Clinical Signs: Kidney function (baseline creatinine established before start of treatment), monitor creatinine and urine protein more frequently if levels appear to be rising

NCCN Grading Scale

Grade Severity	1	2	3 or 4
Renal Toxicity	Creatinine 1.5-2x above baseline or increase >/= 0.3 mg/dl	Creatinine 2-3x above baseline	Creatinine > 3x baseline or > 4.0 mg/dl; dialysis indicated

Managing the IO regimen:	Consider holding IO therapy
irAE management:	Follow creatinine and urine protein ratio every 3-7 days Initiate workup to evaluate potential alternate etiologies Consider nephrology consult if creatinine remains unchanged over 2 weeks
SAVE

Managing the IO regimen:	Hold IO therapy
irAE management:	Follow creatinine and urine protein ratio every 3-7 days Nephrology consultation and consider renal biopsy if feasible prior to starting steroids Initiate prednisone 0.5-1 mg/kg/day if other etiologies are ruled out (recent IV contrast, medications, fluid status, UTI) Treat until symptoms improve to ≤ Grade 1, then taper over 4-6 weeks Persistent Grade 2 beyond 1 week: prednisone/methylprednisolone 1-2 mg/kg/day
SAVE

Managing the IO regimen:	Hold IO therapy
irAE management:	Consider hospitalization Follow creatinine and urine protein ratio every 3-7 days Nephrology consultation and consider renal biopsy if feasible prior to starting steroids Initiate prednisone/methylprednisolone 1-2 mg/kg/day Treat until symptoms improve to ≤ Grade 1, then taper over 4-6 weeks If kidney injury remains > Grade 2 after 4-6 weeks of steroids, consider adding azathioprine, cyclophosphamide (monthly), cyclosporine, infliximab, or mycophenolate
SAVE

Potential symptoms to watch: Radioactive iodine uptake scan can be used to assess cause. Low uptake may indicate thyroiditis, while high uptake may indicate goiter, adenoma, or Graves’ disease

CTCAE 5.0

Grade Severity	1	2	3	4
Hypothyroidism	Asymptomatic Clinical or diagnostic observations only Intervention not indicated	Moderate symptoms Thyroid replacement indicated Limiting instrumental ADLs	Severe symptoms Limiting self-care ADLs Hospitalization indicated	Life-threatening consequences Urgent intervention indicated

*NCCN Does not classify recommendations by Grade. CTCAE Grading is included for documentation proposes for the user of this tool.

Defined as elevated TSH with normal free T4 Managing the IO regimen:	TSH 4-10: continue IO therapy TSH > 10: continue IO therapy
irAE management:	Monitor TSH and free T4 every 4-6 weeks TSH 4-10: continue to monitor thyroid function tests (TFTs) TSH > 10: consider levothyroxine ~1.6 mcg/kg/day with goal of getting TSH to reference range
SAVE

Defined as TSH > 10 with low free T4 and clinical symptoms Managing the IO regimen:	Continue IO therapy
irAE management:	Consider endocrine consultation Initiate thyroid hormone supplementation with levothyroxine, repeating TSH in 4-6 weeks to guide dosing changes Exclude concomitant adrenal insufficiency (morning cortisol level)
SAVE

Defined as suppressed TSH that may be sublicincal if free T4 normal or clinical if high free T4; most patients are asymptomatic but symptoms if present may include palpitations, heat intolerance, restlessness or anxiety, fine tremor, and/or weight loss Managing the IO regimen:	Continue IO therapy
irAE management:	Consider propranolol 10-20 mg q4-6h for symptoms as needed or atenolol or metoprolol as needed until resolution Repeat TFTs in 4-6 weeks If resolved: no further therapy needed If persistent thyrotoxicosis: consider evaluation for Graves disease
SAVE

Please add any notes on symptoms, clinical signs, and other considerations to save with all interventions

Additional irAEs to add?

Click FINISH once you have saved all interventions

Immune-Related Adverse Event (irAE) Management Tool

[Hypophysitis]

[Grade 1] Asymptomatic or mild symptoms; clinical or diagnostic observations only

[Grade 2] Moderate Symptoms

[Grade 3] Severe symptoms or [Grade 4] Life-threatening consequences

Steven-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)

[Grade 1] Asymptomatic or mild symptoms; clinical or diagnostic observations only

[Grade 2] Moderate Symptoms

[Grade 3] Severe symptoms or [Grade 4] Life-threatening consequences

[Grade 1] Asymptomatic or mild symptoms; clinical or diagnostic observations only

[Grade 2] Moderate Symptoms

[Grade 3] Severe symptoms or [Grade 4] Life-threatening consequences

[Grade 1] Asymptomatic or mild symptoms; clinical or diagnostic observations only

[Grade 2] Moderate Symptoms

[Grade 3] Severe symptoms or [Grade 4] Life-threatening consequences

[Grade 1] Asymptomatic or mild symptoms; clinical or diagnostic observations only

[Grade 2] Moderate Symptoms

[Grade 3] Severe symptoms

[Grade 1] Asymptomatic or mild symptoms; clinical or diagnostic observations only

[Grade 2] Moderate Symptoms

[Grade 3] Severe symptoms or [Grade 4] Life-threatening consequences

Asymptomatic/Subclinical Hypothyroidism

Clinical (Overt) Primary Hypothyroidism

Thyrotoxicosis