Journal: Clinical and experimental medicine
This publication is a large case-based systematic analysis of immune checkpoint inhibitor (ICI)–associated immune-related adverse events (irAEs), with a specific focus on multi-organ involvement.
Design and methods
- Data source: Case reports of ICI-related irAEs from PubMed, Web of Science, Cochrane Library, and Embase up to January 2022.
- Population: 2,964 patients with irAEs, including 782 with multi-organ irAEs and 2,182 with single-organ irAEs.
- Comparisons:
- Multi-organ vs single-organ irAEs: baseline characteristics, toxicity patterns, severity, outcomes.
- Within multi-organ irAEs: high- vs low-dose glucocorticoids, separately for severe and non-severe cases.
- Multivariable analysis: identification of mortality-associated organ toxicities.
Key findings
1. Frequency and phenotype of multi-organ irAEs
- Proportion: Multi-organ irAEs constituted roughly one quarter of reported irAEs.
- Demographics: No significant age or sex differences vs single-organ cases.
- Toxicity profile:
- Higher rates of cardiovascular, thyroid, and skin toxicities.
- Higher proportion of severe adverse reactions.
- Higher overall mortality.
2. Common organ combinations
Frequent multi-organ constellations included:
- Cardiac + neurological
- Cardiac + pulmonary
- Thyroid + pituitary
- Cardiac + hepatic
- Gastrointestinal + skin
These patterns underscore the clustering of cardiac toxicity with other critical-organ events and of endocrine toxicities with each other.
3. Glucocorticoid dosing and outcomes
Severe multi-organ irAEs:
- No age or sex differences between high-dose and low-dose steroid groups.
- High-dose glucocorticoids were associated with significantly higher mortality.
Non-severe multi-organ irAEs:
- No significant differences in mortality, prognosis, age, or sex between high- and low-dose glucocorticoid groups.
Taken together, escalated steroid dosing did not confer a prognostic advantage and may be harmful in severe multi-organ irAEs.
4. Mortality risk factors
On multivariate logistic regression in multi-organ irAEs, the following organ toxicities were independently associated with higher mortality (OR > 1, statistically significant):
- Cardiovascular toxicity
- Pulmonary toxicity
- Hepatotoxicity
- Myositis
These toxicities mark a particularly high-risk subgroup.
Clinical implications for oncology practice
- Multi-organ irAEs represent a clinically distinct, higher-risk phenotype with greater severity and mortality than single-organ irAEs.
- Cardiac, pulmonary, hepatic, and muscular (myositis) involvement should trigger heightened concern, intensive monitoring, and early multidisciplinary input.
- More steroid is not necessarily better: in severe multi-organ irAEs, high-dose glucocorticoids were associated with worse survival, arguing for individualized dosing rather than reflexive maximal dosing.
- For non-severe multi-organ irAEs, high-dose steroids did not improve outcomes, suggesting lower doses may be adequate in many cases.
Overall, the study supports risk-adapted management of ICI toxicities, with careful attention to organ pattern and severity, and challenges the assumption that more aggressive steroid therapy uniformly improves outcomes in severe multi-organ irAEs.