Mechanisms outpacing medicine in autoinflammatory diseases

Area of Science:

• Genetics and immunology
• Molecular medicine
• Systems biology

Background:

• Autoinflammatory diseases are increasingly understood at genetic and pathway levels.
• Therapeutic predictability has not kept pace with molecular diagnostics.
• Monogenic disorders present challenges in predicting disease progression and treatment response.

Purpose of the Study:

• To examine the misalignment between molecular diagnosis and clinical outcomes in autoinflammation.
• To propose a framework for genotype-informed therapeutic decision-making.
• To emphasize integrating multiple factors beyond genotype for effective treatment.

Main Methods:

• Review of current literature on autoinflammatory diseases.
• Analysis of therapeutic challenges in type I interferonopathies, inflammasome-related disorders, and NF-κB-centered diseases.
• Development of a conceptual framework for treatment strategy.

Main Results:

• Molecular diagnosis alone is insufficient for predicting treatment efficacy in autoinflammatory diseases.
• Similar phenotypes can result from different genetic defects, and vice versa.
• The initiating genetic lesion may not align with the current drivers of inflammation and tissue injury.

Conclusions:

• Treatment decisions for autoinflammation should be genotype-informed, not solely genotype-determined.
• A phenotype-weighted, organ-prioritized, and time-sensitive framework is proposed.
• This approach aims to better align mechanism-based therapies with clinical outcomes and patient needs.