# Still’s Disease and Autoinflammation: Positioning an Inflammatory Syndrome on the Autoinflammation-Autoimmunity Spectrum

## TL;DR

Still’s disease is positioned on a spectrum between autoinflammation and autoimmunity, with insights into immune mechanisms and treatment strategies.

## Contribution

The paper positions Still’s disease as a spectrum disorder with variable innate-adaptive immune contributions, guiding personalized treatment approaches.

## Key findings

- Still’s disease involves complex innate-adaptive immune interactions, including type I interferon signaling and neutrophil extracellular traps.
- mTORC1 acts as a central hub integrating cytokine signals in Still’s disease.
- Therapies targeting IL-1, IL-6, and emerging agents like IL-18 binding protein show promise in treating refractory cases.

## Abstract

Still’s disease exemplifies systemic inflammatory disorders existing on a continuum between autoinflammation and autoimmunity. This review examines Still’s disease through this spectrum lens, integrating recent advances in pathogenesis, clinical heterogeneity, and therapeutic approaches.

Emerging mechanistic insights reveal complex innate-adaptive immune interactions. Type I interferon signalling and neutrophil extracellular trap formation drive inflammation, while hyperferritinemia actively perpetuates disease through Msr1-mediated signaling. mTORC1 has emerged as a central integration hub converging multiple cytokine signals. Adaptive mechanisms increasingly contribute to complications: both macrophage activation syndrome and lung disease demonstrate IFNγ-dominant pathology with T cell hyperactivation. Clinical phenotyping identifies distinct patient clusters—from hyperferritinemic monocyclic to catastrophic multiorgan phenotypes—reflecting varying innate-adaptive contributions. Current classification criteria permit considerable diagnostic latitude and may inadvertently group mechanistically distinct conditions under a single diagnostic label. IL-1 and IL-6 receptor blockade remain therapeutic cornerstones, with evidence supporting early intervention during a window of opportunity. Novel approaches including IL-18 binding protein, JAK inhibitors, and IFNγ blockade show promise in refractory disease.

Still's disease predominantly reflects autoinflammatory pathology driven by innate immune dysregulation, yet adaptive mechanisms contribute meaningfully to disease heterogeneity and complications. Recognition as a spectrum disorder—with variable innate-adaptive contributions across patients and disease phases—supports unification of pediatric and adult forms, guides mechanistically targeted therapies, and emphasizes the need for biomarker-driven patient stratification to enable personalized treatment approaches.