Immune Checkpoint Inhibitor Adverse Event Management — Part 2: Dermatologic, Gastrointestinal, and Hepatic irAEs

Dermatologic Immune-Related Adverse Events

Dermatologic irAEs are the most common class of irAEs overall, occurring in approximately 30% to 40% of patients on anti-PD-1/PD-L1 monotherapy and up to 50% of patients on combination immunotherapy. They are typically among the earliest irAEs to manifest, often appearing within the first 2 to 6 weeks of therapy. While the majority of cutaneous irAEs are mild and manageable, severe presentations including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening.^{1 2 3}

Maculopapular Rash / Dermatitis

Maculopapular rash is the most common cutaneous irAE. It typically presents as a diffuse, erythematous, morbilliform eruption affecting the trunk and extremities. Lichenoid, eczematous, and psoriasiform patterns are also observed.

Grading

Management by Grade

Pruritus (Without Rash)

Pruritus without visible rash occurs in approximately 10% to 20% of ICI-treated patients. It can significantly impair quality of life.

Bullous Pemphigoid

Bullous pemphigoid is an autoantibody-mediated blistering disease that occurs more frequently with anti-PD-1/PD-L1 agents (approximately 1% incidence). It typically presents with tense bullae on an erythematous or urticarial base, often with intense pruritus, and typically appears later in the treatment course (median 4–6 months).²

Workup:

• Dermatology consultation
• Skin biopsy of lesional skin (H&E) and perilesional skin (direct immunofluorescence showing linear IgG and C3 at the dermal-epidermal junction)
• Serum BP180 and BP230 antibody titers

Management:

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

SJS and TEN are rare but potentially fatal irAEs with reported mortality of 10% for SJS and 30% or higher for TEN. They represent a dermatologic emergency.^{1 2}

Classification:

• SJS: epidermal detachment involving < 10% BSA
• SJS/TEN overlap: 10%–30% BSA detachment
• TEN: > 30% BSA detachment

Clinical features: Mucocutaneous involvement (oral, ocular, genital mucosa); targetoid lesions with central necrosis; positive Nikolsky sign; systemic symptoms (fever, malaise).

Management:

1. Permanently discontinue ICI immediately
2. Admission to burn unit or ICU with dermatology and ophthalmology consultation
3. Withdraw all potential offending medications (not only ICI but all suspect drugs)
4. Supportive care: wound care (similar to burn management); temperature regulation; fluid and electrolyte management; nutritional support; pain management
5. Systemic corticosteroids: methylprednisolone 1–2 mg/kg/day IV; role is controversial in drug-induced SJS/TEN but recommended in ICI-associated cases given the immune mechanism
6. IVIG: 1–2 g/kg total dose over 3–4 days may be considered, particularly for TEN
7. Cyclosporine: 3–5 mg/kg/day in divided doses has shown benefit in some SJS/TEN series
8. Monitor for secondary infection (leading cause of death), sepsis, electrolyte derangements, fluid losses
9. Ophthalmology consultation is mandatory – ocular involvement can cause scarring, symblepharon, and permanent visual impairment

Vitiligo

Vitiligo (depigmentation) occurs in 5% to 25% of melanoma patients treated with anti-PD-1 agents. It is considered a favorable prognostic sign, associated with better tumor response and survival. Vitiligo does not require ICI interruption or corticosteroid therapy. Cosmetic management with camouflage products and sun protection is appropriate. Referral to dermatology for cosmetic concerns is reasonable.⁴

Gastrointestinal Immune-Related Adverse Events: Colitis and Diarrhea

Immune-mediated colitis is one of the most common and clinically significant irAEs. It occurs in approximately 8% to 12% of patients on anti-CTLA-4 monotherapy, 1% to 3% on anti-PD-1/PD-L1 monotherapy, and 15% to 20% on combination regimens. Colitis carries risk of perforation (1%–3% in severe cases) and is one of the leading causes of irAE-related mortality.^{1 2 3 5}

Grading of Diarrhea and Colitis

Differential Diagnosis

Before initiating immunosuppressive treatment for suspected immune-mediated colitis, the following must be excluded:^{1 3}

• Clostridioides difficile infection: Stool C. difficile toxin PCR or toxin assay (mandatory in all cases)
• CMV colitis: CMV PCR (blood) and immunohistochemistry on colonic biopsies (particularly important in steroid-refractory colitis)
• Other infectious diarrhea: Stool culture, ova and parasites, Giardia antigen, stool multiplex GI pathogen panel
• Medication-related: Other drugs causing diarrhea (antibiotics, laxatives, metformin, TKIs)
• Disease progression: New peritoneal or GI metastases
• Other causes: Celiac disease, IBD flare (in patients with preexisting IBD), ischemic colitis, radiation enteritis

Workup

Grade-Based Management of Immune-Mediated Colitis/Diarrhea

Infliximab for Steroid-Refractory Colitis

• Dose: 5 mg/kg IV as a single dose; may repeat once at 2 weeks if partial response
• Onset: clinical improvement typically within 1–3 days
• Pre-infusion requirements: Negative hepatitis B serology (HBsAg, anti-HBc, anti-HBs); QuantiFERON-TB Gold or PPD (may treat empirically for latent TB if urgently needed); rule out bowel perforation
• Contraindications: Active sepsis or perforation; hepatic irAE (infliximab is hepatotoxic)
• If infliximab-refractory or contraindicated: Vedolizumab 300 mg IV (gut-selective anti-integrin; may be preferred if concurrent hepatic irAE); may repeat at weeks 2 and 6; slower onset than infliximab but avoids systemic immunosuppression⁵

CMV Colitis Superimposed on irAE Colitis

CMV reactivation can occur in the setting of immunosuppression for irAE colitis and should be suspected when:

• Colitis is refractory to corticosteroids and infliximab
• Colitis worsens after initial improvement
• Deep ulcerations on colonoscopy with viral inclusions on biopsy

Diagnosis: CMV PCR (blood); CMV immunohistochemistry on colonic biopsies (more sensitive than H&E alone)

Treatment: Ganciclovir 5 mg/kg IV every 12 hours (or valganciclovir 900 mg PO BID if oral tolerated) for 14–21 days; continue immunosuppressive treatment for the underlying irAE concurrently¹

Hepatic Immune-Related Adverse Events: Immune-Mediated Hepatitis

Immune-mediated hepatitis occurs in approximately 5% to 10% of patients on anti-CTLA-4 monotherapy, 1% to 4% on anti-PD-1/PD-L1 monotherapy, and 15% to 20% on combination regimens. It is the second most common cause of irAE-related death after myocarditis. Immune-mediated hepatitis is primarily hepatocellular but can occasionally present with a cholestatic or mixed pattern.^{1 2 3}

Grading of Hepatic irAEs

Note: If baseline LFTs were elevated (e.g., due to liver metastases), grading should be based on the change from the patient’s baseline rather than the institutional ULN.

Differential Diagnosis

• Viral hepatitis (HAV, HBV, HCV, HEV; CMV, EBV in immunosuppressed)
• Drug-induced liver injury (other medications, herbal supplements, acetaminophen)
• Hepatic metastases (progressive disease)
• Biliary obstruction
• Alcohol-related liver disease
• Autoimmune hepatitis (preexisting vs de novo)
• Hepatic vein thrombosis (Budd-Chiari)

Workup

Grade-Based Management of Immune-Mediated Hepatitis

Key Points for Hepatic irAE Management

• Infliximab is contraindicated in immune-mediated hepatitis due to its own hepatotoxicity risk and potential to worsen hepatic injury.^{1 3}
• Mycophenolate mofetil is the first-line steroid-sparing agent for hepatic irAEs.
• Azathioprine should be avoided as a substitute for MMF in the acute setting due to its potential hepatotoxicity and slower onset of action.
• Rising bilirubin and INR indicate hepatic decompensation and mandate aggressive management.
• Ursodeoxycholic acid (13–15 mg/kg/day) may be considered for cholestatic patterns.
• Patients with hepatic metastases at baseline may have fluctuating LFTs unrelated to irAEs; clinical context and trend (rapid rise vs gradual change) help differentiate.
• Unlike idiopathic autoimmune hepatitis, ICI-induced hepatitis typically does not require lifelong immunosuppression; most cases resolve with an appropriate corticosteroid course and taper.

References