What is the best course of action to handle a rash biopsied after treatment with Opdivo (nivolumab) and Yervoy (ipilimumab)?

Management of Immune-Related Rash After Opdivo and Yervoy Treatment

The best course of action is to grade the severity of the biopsied rash using body surface area (BSA) and symptom burden, then treat according to a stepwise protocol: Grade 1 (<10% BSA) continues immunotherapy with topical steroids; Grade 2 (10-30% BSA) may continue therapy with medium-potency topical steroids and oral antihistamines; Grade 3 (>30% BSA or Grade 2 with severe symptoms) requires holding immunotherapy and initiating systemic corticosteroids at 0.5-1 mg/kg prednisone; Grade 4 requires permanent discontinuation, hospitalization, and IV methylprednisolone 1-2 mg/kg. 1

Critical First Steps: Rule Out Life-Threatening Conditions

Before implementing treatment, you must immediately exclude dermatologic emergencies that require permanent drug discontinuation and hospitalization 1:

• Perform thorough physical examination including all mucosal surfaces (eyes, nares, oropharynx, genitals, perianal area), assess for lymphadenopathy, facial/extremity swelling, pustules, blisters, erosions, and areas of dusky erythema painful to palpation 1
• Obtain laboratory workup including complete blood count with differential (looking for eosinophilia), liver function tests, and kidney function to rule out DRESS syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis 1
• Review biopsy results with dermatology to confirm immune-mediated dermatitis versus severe cutaneous adverse reactions (SCARs) 1

The FDA label warns that Yervoy (ipilimumab) combined with Opdivo (nivolumab) can cause bullous dermatitis, Stevens-Johnson syndrome, TEN, and DRESS—all requiring permanent discontinuation 2. Fatal cases have been reported with combination therapy 3.

Grade-Based Treatment Algorithm

Grade 1: Rash <10% BSA

• Continue immunotherapy without interruption 1
• Apply topical emollients liberally multiple times daily (Diprobase, Epaderm, Cetraben, Hydromol) 1, 4
• Use mild-to-moderate potency topical corticosteroids (triamcinolone 0.1% or equivalent) to affected areas once daily 1
• Add oral antihistamines for pruritus (cetirizine 10mg or loratadine 10mg daily preferred over sedating diphenhydramine) 1, 5
• Counsel patients to avoid skin irritants and use soap substitutes instead of traditional soaps 1

Grade 2: Rash 10-30% BSA

• Consider holding immunotherapy and monitor weekly; if no improvement after 4 weeks, regrade as Grade 3 1
• Escalate to medium-to-high potency topical corticosteroids (clobetasol 0.05% or betamethasone valerate 0.1%) applied twice daily 1
• Continue topical emollients and oral antihistamines 1
• Consider initiating oral prednisone 0.5-1 mg/kg daily if symptoms are substantial or rash is intolerable, tapering over 4 weeks 1
• Obtain dermatology consultation for consideration of repeat biopsy if diagnosis uncertain 1

The ASCO guideline emphasizes that Grade 2 severity should be based on BSA, tolerability, morbidity, and duration—not just BSA alone 1. The ESMO guideline notes that diffuse but light rash without additional symptoms may warrant continuing therapy 1.

Grade 3: Rash >30% BSA or Grade 2 with Severe Symptoms

• Hold immunotherapy immediately until rash improves to Grade 1 1
• Initiate systemic corticosteroids: oral prednisone 1 mg/kg/day (or IV methylprednisolone 0.5-1 mg/kg if severe), tapering over at least 4 weeks 1
• Continue high-potency topical corticosteroids, oral antihistamines, and emollients 1
• Obtain urgent dermatology consultation to determine appropriateness of resuming immunotherapy 1
• Consider phototherapy for severe pruritus refractory to other measures 1
• May consider resuming immunotherapy once downgraded to Grade 1 and prednisone dose below 10 mg/day, with close dermatology follow-up 1

For pruritus without visible rash at Grade 3, consider gabapentin, pregabalin, aprepitant, or dupilumab 1.

Grade 4: Skin Sloughing >30% BSA with Systemic Symptoms

• Immediately discontinue immunotherapy permanently 1
• Admit patient urgently with direct oncology and dermatology involvement 1
• Initiate IV methylprednisolone 1-2 mg/kg with slow tapering when toxicity resolves 1
• Monitor closely for progression to Stevens-Johnson syndrome, TEN, or DRESS 1
• Consider alternative antineoplastic therapy if skin toxicity does not resolve to Grade 1; only restart immunotherapy if it is the patient's only treatment option and only after resolution to Grade 1 with close dermatology follow-up 1

Special Considerations for Combination Opdivo/Yervoy Therapy

The FDA label reports that immune-mediated rash occurred in 28% of patients receiving Yervoy 3 mg/kg with Opdivo 1 mg/kg, with Grade 3 rash in 4.8% 2. Importantly:

• Systemic corticosteroids were required in 100% of patients with immune-mediated rash on combination therapy 2
• Rash resolved in 84% of affected patients 2
• Of patients who had therapy withheld, 15 of 18 reinitiated treatment after improvement, but 8 experienced recurrence 2

This high recurrence rate (53%) after rechallenge underscores the importance of careful monitoring if immunotherapy is resumed 2.

Critical Pitfalls to Avoid

Do not use high-potency topical steroids on the face or intertriginous areas (groin, axillae) due to increased risk of skin atrophy; use hydrocortisone 1% in these locations instead 1, 5.

Do not escalate methylprednisolone above 2 mg/kg/day—there is no additional benefit and increased toxicity risk 1.

Do not assume all rashes are benign—the combination of nivolumab and ipilimumab carries higher risk for severe cutaneous adverse reactions including fatal TEN compared to monotherapy 3. One case report documented TEN with 60% BSA involvement and multiorgan failure leading to death on day 4 after the second cycle of combination therapy 3.

Do not underprescribe emollients—patients require 200-400g per week for adequate coverage, and underprescribing leads to treatment failure 4.

Monitoring and Follow-Up

• Weekly monitoring for Grade 2 rash to assess for progression 1
• Serial clinical photography to objectively track changes 1
• Watch for signs of secondary infection (increased warmth, purulence, worsening erythema) which may require systemic antibiotics 5
• Reassess after 2 weeks of treatment; if no improvement, escalate therapy or obtain dermatology consultation 5

The evidence shows that using immunosuppressive agents for managing immune-related toxicities does not negatively affect clinical outcomes from checkpoint inhibitor therapy 1, so do not hesitate to treat aggressively when indicated.