Pembrolizumab and nivolumab are PD-1 checkpoint inhibitors. A patient develops immune-related pneumonitis grade 3 (severe). What is the FIRST-LINE management, and why are systemic steroids used rather than drug-specific antidotes?

• A High-dose systemic corticosteroids (1–2 mg/kg/day prednisone equivalent) to suppress the T-cell-mediated autoimmune inflammatory response in the lung; no drug-specific antidote exists for immune checkpoint inhibitors ✓
• B Ipilimumab (anti-CTLA-4) added to block the different checkpoint; no antidote exists for PD-1 inhibitors
• C Antihistamines and epinephrine as this represents drug hypersensitivity, not immune checkpoint toxicity
• D Infliximab (anti-TNF) as first-line followed by corticosteroids if no response within 24 hours

Explanation

Immune-related adverse events (irAEs) from PD-1/PD-L1 checkpoint inhibitors result from T-cell hyperactivation and loss of self-tolerance — the same mechanism that causes antitumor efficacy applied to normal tissues. Grade 3 (severe) pneumonitis requires permanent discontinuation of the checkpoint inhibitor and immediate high-dose systemic corticosteroids (1–2 mg/kg/day prednisone equivalent), which suppress the pathogenic T-cell response. There is no specific antidote because the drug's Fc portion does not have a receptor target that could be blocked. For steroid-refractory pneumonitis, additional immunosuppression with infliximab or mycophenolate is used. Grade 1–2 cases may be managed with drug hold and lower-dose steroids.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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