For severe or life-threatening immune-related adverse effects of checkpoint inhibitors, consult with the prescribing oncologist, stop checkpoint inhibitor therapy immediately, and start high-dose corticosteroids (prednisone 1-2 mg/kg/day or equivalent).
Diagnosis Overview:
Monoclonal antibodies directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4), such as ipilimumab and tremelimumab; programmed cell death-1 (PD-1), such as nivolumab and pembrolizumab; and programmed cell death ligand-1 (PDL-1), such as atezolizumab, avelumab, and durvalumab, collectively known as the immune checkpoint inhibitors (ICIs), are effective in the treatment of various advanced solid organ malignancies, as well as lymphomas. During therapy with these novel agents, a unique set of adverse effects may develop called immune-related adverse events (irAEs). These can be of varying degrees of severity and include:
- Cardiac: myocarditis, acute vascular events, pericardial disease, and atrial fibrillation, among others.
- Endocrine: hyper- and hypothyroiditis, hypophysitis, and worsening diabetes.
- Gastrointestinal (GI): colitis, hepatitis, and pancreatitis.
- Musculoskeletal: myositis, inflammatory arthritis, and arthralgias.
- Neurologic events: myasthenia gravis, neuropathies (including motor axonal neuropathy), meningitis, encephalitis, and myelitis.
- Pulmonary: pneumonitis and interstitial lung disease.
- Renal: acute kidney injury, kidney failure, and nephritis.
- Numerous cutaneous side effects have been recognized, including lichenoid reactions, eczema, vitiligo, maculopapular / exanthematous eruptions, psoriasis, bullous pemphigoid, granulomatous reactions, drug-induced hypersensitivity syndrome, true Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN), and an SJS / TEN-like reaction, which has been recently named progressive immunotherapy-related mucocutaneous eruption (PIRME). See cutaneous adverse effects of immune checkpoint inhibitors.
- Other irAEs include iridocyclitis and lymphadenopathy.
In one meta-analysis, colitis was the most frequent severe irAE in patients receiving anti-CTLA-4 antibodies, seen in 70% of deaths with those agents, whereas pneumonitis (35%), hepatitis (22%), and neurotoxic effects (15%) were seen in deaths associated with PD-1 or PD-L1 antibodies. The highest fatality rates are associated with irAE-associated myocarditis.
IrAEs of any grade occur in up to 60% of patients receiving ipilimumab (an anti-CTLA-4 antibody), and 10%-30% of these are considered serious. IrAEs with ipilimumab appear to be dose dependent. Diarrhea and colitis are the most common and occur within 8-12 weeks of starting treatment. Less common irAEs with this therapy include pruritus, hepatitis, and endocrinopathies.
IrAEs related to PD-1 inhibitors are less frequent in comparison. Only 10% of recipients will have severe irAEs. Less severe irAEs, such as fatigue, headache, arthralgias, rash, pruritus, pneumonitis, diarrhea, colitis, and endocrinopathies, occur in between 5% and 20% of recipients within the first 6 months of therapy. The most common irAEs with nivolumab are endocrinopathies (thyroiditis), pneumonitis, hepatitis, diarrhea, and colitis. There has been a case in which severe autoimmune enteritis developed in an otherwise healthy infant after in-utero exposure to pembrolizumab.
In a large meta-analysis of non-small cell lung cancer (NSCLC) patients, 27% of patients on anti-CTLA therapy and 17% of patients on anti-PD-1 or PDL-1 therapy reported high-grade irAEs.
Life-threatening reactions remain rare and are estimated to occur with an incidence between 0.3% and 1.3%; they often occur early in the course of treatment.
Besides varying by ICI type, irAEs are reported to vary by cancer type. GI and dermatologic events have been reported to occur more commonly in melanoma patients, whereas myalgia and arthritis have been reported more commonly in NSCLC patients.
