To examine the disconnect between advancements in understanding autoinflammatory diseases at the genetic and pathway levels and the lack of parallel therapeutic predictability, highlighting its significance.
Approach:
Key Findings:
Monogenic autoinflammatory diseases often do not follow a linear gene-to-pathway-to-therapy model; for example, distinct molecular defects can lead to similar clinical phenotypes.
Disruption of the same pathway may lead to different organ involvement and treatment responses, as seen in various case studies.
Therapeutic response is influenced by genotype, organ involvement, disease stage, and tissue reversibility, which complicates treatment.
Interpretation:
Treatment should be genotype-informed rather than solely genotype-determined, integrating various clinical factors for better alignment with real-world outcomes.
Limitations:
The review does not provide specific therapeutic recommendations, which limits practical application, and highlights the complexity of treatment decision-making without offering a definitive solution.
Conclusion:
A phenotype-weighted, organ-prioritized, and time-sensitive framework may improve alignment of mechanism-based therapy with clinical outcomes, emphasizing its potential impact.
