Table 4: General guidelines for recommended management of irAEs [26]. (adapted from YERVOY REMS 2011).

SiteSigns and symptomsManagement

SkinEvaluate patients for signs and symptoms of pruritus, rash or other skin toxicities
Rule out non-irAE causes
Grade 1 or 2: Mild to moderate, localized; papules/pustules covering <10%–30% of body surface
(i) Topical thick moisturizers and oatmeal baths, antihistamines, topical corticosteroids should be added if no response
(ii) If no improvement after 1-2 weeks with topical corticosteroids, treat with oral corticosteroid therapy (e.g., prednisone 1 mg/kg qd or equivalent)  
Grade 3 or 4: Intense or widespread >30%; skin sloughing <10%–30% of body surface; epidermal or mucus membrane detachment.
(i) For grade 3 rash, potent topical corticosteroid creams may be used first, but systemic corticosteroids may be required
(ii) Administer high-dose systemic corticosteroid therapy (e.g., prednisone 1-2 mg/kg PO or methylprednisolone 1-2 mg/kg IV or equivalent depending on severity, administered qd or bid); once symptoms are controlled, initiate corticosteroid taper ≥1 month
(iii) Withhold ipilimumab dosing in patients with grade 3 or 4 skin toxicities
(iv) Permanently discontinue ipilimumab in patients with grade 4 rash (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis or rash complicated by full thickness dermal ulceration or necrotic, bullous or hemorrhagic manifestations)

GIAssess patients for changes in bowel habits and for the following signs and symptoms: diarrhea, abdominal pain, blood or mucus in stool with or without fever, peritoneal signs consistent with bowel perforation and ileus
Rule out infectious or alternate etiologies  
A biopsy through endoscopy may be performed as clinically indicated; provide appropriate symptomatic treatment, and withhold or continue ipilimumab dosing as clinically appropriate
Grade 1 or 2: <4–6 stools/day over baseline, IV fluids <24 hours, abdominal pain, mucus or blood in stool
(i) Symptomatic management (dietary modifications and loperamide or diphenoxylate) and increase frequency of monitoring
(ii) Grade 2 may be initially treated with oral diphenoxylate hydrochloride and atropine sulfate four times per day and budesonide 9 mg once per day or divided three times per day
(iii) If symptoms persist (5–7 days) or relapse, treat with corticosteroid therapy (e.g., prednisone 1 mg/kg qd or equivalent)   
Grade 3 or 4: 7 stools/day over baseline or more, IV fluids 24 hours, hospitalization, abdominal pain, fever, life-threatening consequences
(i) Administer 1–2 mg/kg methylprednisolone or equivalent and then move forward with ensuring differential diagnosis
(ii) Once diarrhea and other symptoms are controlled, corticosteroid dose should be gradually tapered over 1 month; if there is no improvement within 5 days, or relapse occurs after corticosteroids, administer a single dose of infliximab 5 mg/kg unless contraindicated; infliximab should not be used if perforation or sepsis is present; for patients with concomitant hepatitis, mycophenolate mofetil can be used instead
(iii) Withhold ipilimumab dosing for moderate reactions until improvement to mild severity or complete resolution; for severe reactions (grade 3 or 4), permanently discontinue ipilimumab

EndocrineNon-specific symptoms include fatigue, headache, changes in mental status, abdominal pain, unusual bowel habits and hypotension.
Undertake appropriate work-up (TSH, free T4, ACTH and morning cortisol); consider co-syntropin stimulation test, LH, FSH, testosterone, and prolactin; radiographic imaging [e.g., MRI] with pituitary cuts should be performed to assess size of pituitary gland in patients with symptoms suggestive of hypophysitis)
Endocrinopathy not suggestive of adrenal crisis   
(i) For patients with abnormal endocrine work up, grade 1 or 2 endocrine toxicity without adrenal crisis may resolve spontaneously if a patient has no or minimal symptoms but should be monitored closely, possibly with guidance from an endocrinologist; otherwise, short-term, high-dose corticosteroids (e.g., dexamethasone 4 mg every six hours or equivalent) with relevant hormone replacement (e.g., levothyroxine, hydrocortisone, or sex hormones)
(ii) Patients with symptoms suggestive of hypophysitis require prompt corticosteroid therapy   
Adrenal crisis: severe dehydration, hypotension, or shock   
(i) Immediately initiate intravenous corticosteroids with mineral corticoid activity (e.g., methylprednisolone)
(ii) When condition stabilizes, initiate endocrine work up and start appropriate hormone replacement therapy
Moderate reactions or symptomatic endocrinopathy(i) Withhold ipilimumab until complete resolution or stable on hormone replacement therapy
(ii) Patients unable to have their corticosteroid dose reduced to 7.5 mg prednisone or equivalent per day should permanently discontinue ipilimumab
(iii) Consider long-term hormone replacement therapy as necessary

HepaticRun LFTs before each infusion or more frequently if indicated.
Monitor patients for any signs of hepatitis.
Rule out non-inflammatory causes of hepatotoxicity:
Infections, disease progression, or medications and monitor until resolution (e.g., at 3-day intervals). Provide appropriate symptomatic treatment and withhold or continue ipilimumab dosing as clinically appropriate
AST or ALT >2.5x–5.0x ULN or total bilirubin >1.5x–3x ULN
(i) Withhold the dose of ipilimumab
(ii) Check LFTs every day for 3 consecutive days; if LFT improvement to grade 1, resume routine monitoring of LFTs and continue ipilimumab
(iii) If no improvement in the LFTs, administer corticosteroid treatment (e.g., prednisone 1-2 mg/kg/day) and continue to monitor closely
(iv) Skip the next dose of ipilimumab until event resolves with no requirement for corticosteroids   
AST or ALT >5x ULN or total bilirubin >3x ULN
(i) Permanently discontinue ipilimumab
(ii) Treat with high-dose intravenous corticosteroid therapy (e.g., methylprednisolone 2 mg/kg qd or bid or equivalent) to control initial symptoms
(iii) LFTs should be assessed daily
(iv) If LFTs are stable or declining for 5 consecutive days, assess LFTs weekly until normalization; once symptoms have resolved and LFT elevations are normalized, initiate corticosteroid taper over ≥1 month; elevations in LFTs during taper may be managed with increase in corticosteroid dose or slower taper
(v) If no response to corticosteroid therapy within 3–5 days, or for those with an LFT elevation during corticosteroid tapering that is not responsive to an increase in dose of corticosteroids, addition of immunosuppressive therapy with mycophenolate mofetil can be considered after a gastroenterology or hepatology consult
(vi) Patients receiving immunosuppression for more than 4 weeks should be evaluated for prophylaxis of opportunistic infections per institutional guidelines

OcularAssess patients for uveitis, iritis or episcleritisAdminister corticosteroid drops with guidance from ophthalmology consultation; systemic corticosteroids should be considered in more severe cases

NeurologicEncourage patient reporting of changes in muscle weakness or sensory alternations
Patient may present with muscle weakness or sensory neuropathies lasting >5 days or motor neuropathies confirmed by physical examination
Rule out non-inflammatory causes:
Disease progression, infections (e.g., Lyme disease), metabolic syndromes, and medications (e.g., taxanes or platinum salts
Grade 1: Asymptomatic, clinical observations only
(i) Treat symptoms per neurological consult recommendations
(ii) Complete diagnostic testing: electromyogram and nerve conduction studies
(iii) Continue ipilimumab
(iv) Continue close monitoring  
Grade 2: Moderate symptoms, limiting instrumental ADL
(i) Treat symptoms per neurological consult recommendations
(ii) Complete diagnostic testing: electromyogram and nerve conduction studies
(iii) Hold/delay ipilimumab until resolution to grade ≤1 
Grade 3 or 4: Severe symptoms, limiting self-case ADL, life-threatening consequences
(i) Treat symptoms per neurological consult recommendations
(ii) Complete diagnostic testing: electromyogram and nerve conduction studies
(iii) Consider intravenous corticosteroids (e.g., methylprednisolone 2 mg/kg qd or bid equivalent)
(iv) Discontinue ipilimumab
(v) If patient is not clinically stable or has atypical symptoms then hospitalize and administer IV corticosteroids and IV immunoglobulin or other immunosuppressive therapies as clinically appropriate

ALT: alanine aminotransferase; AST: aspartate aminotransferase; bid: twice daily; irAE: immune-related adverse event; IV: intravenous; LFTs: liver function tests; MRI: magnetic resonance imaging; PO: oral; qd: once daily; ULN: upper limit of normal.