Arthritis Research & Therapy has published an overarching review of Still’s disease – claiming it to be a single acquired and complex autoinflammatory disease in which both pediatric and adult forms share core pathogenic mechanisms, genetic associations and clinical presentations, with minor differences between children and adults who are afflicted. 

Key Takeaways

• sJIA and AOSD are a single disease — ‘Still’s disease’. Age-based classification is a historical artifact; unified diagnostic and therapeutic frameworks endorsed by EULAR/PReS, FDA and ACR  attest to this unification.
• Core pathogenesis is shared: NLRP3/NLRC4 inflammasome → IL-1β/IL-18 → neutrophil/NET activation → S100 protein amplification → cytokine storm. A biphasic model explains transition from systemic disease to chronic arthritis via adaptive immune activation.
• IL-18 may be the most diagnostically informative biomarker for SD, reliably distinguishing Still’s from sepsis, secondary HLH, malignancy-associated hyperinflammation, and other autoinflammatory diseases. It should be interpreted within a multimarker framework (ferritin, IFN-γ, IL-6, S100 proteins), not used in isolation. But IL-18 levels significantly decline with aging.
• Rare HLH-associated variants (UNC13D, STXBP2) are enriched in SD and may independently predispose to MAS. Atypical or refractory Still’s presentations — particularly in young or consanguineous patients — warrant genetic evaluation to exclude monogenic autoinflammatory disease mimics.

Still’s disease (SD) is now firmly established as a single acquired autoinflammatory condition spanning childhood to adulthood. What was historically separated into systemic juvenile idiopathic arthritis (sJIA) in children and adult-onset Still’s disease (AOSD) in adults reflects an arbitrary age-based classification rather than a true biological distinction. Multicenter clinical studies and meta-analyses confirm that sJIA and AOSD share nearly identical clinical phenotypes, laboratory profiles, cytokine signatures, and treatment responses to IL-1 and IL-6 inhibition. The 2023 EULAR/PReS recommendations and an emerging international treatment guideline have formally endorsed the unified term ‘Still’s disease.’

Minor clinical differences exist: rash and arthritis are reported more frequently in sJIA, while AOSD patients more commonly report serositis, pharyngitis, myalgia, and lymphadenopathy — though these differences may partly reflect developmental limitations in pediatric symptom reporting rather than true biological divergence.

The pathogenic cascade in SD begins with pathogen (or damage) associated molecular patterns (PAMPs/DAMPs) activating macrophages and monocytes via TLR-4 and TLR-9, triggering NLRP3 and NLRC4 inflammasome activation. Downstream caspase-1 cleavage releases active IL-1β and IL-18, the central cytokines driving the early febrile innate immune phase. Key downstream events include:

• IL-18 (originally named ‘IFN-γ inducing factor’) drives NK cell and T-cell activation, IFN-γ production, and — critically — is the primary mediator of macrophage activation syndrome (MAS). Elevated IL-18/IL-6 and IL-18/CRP ratios in active disease signal MAS risk in both sJIA and AOSD.
• Neutrophil activation with enhanced NET formation creates a pro-inflammatory feedback loop: IL-18 itself promotes NET formation by enhancing calcium influx into neutrophils, amplifying the innate immune response.
• S100A8/A9 (calprotectin/MRP8-14) and S100A12, released from activated myeloid cells, function as DAMPs signaling via TLR-4 and RAGE, further amplifying cytokine gene expression. Both are profoundly elevated in active sJIA and AOSD.
• Elevated ferritin — driven by macrophage activation via IL-1β, IL-6, and IFN-γ — serves as both a marker and amplifier of inflammation through NF-κB activation. Glycosylated ferritin is markedly reduced in active AOSD and aids differential diagnosis from other hyperferritinemic states.

A biphasic model explains chronicity: persistent cytokine stimulation promotes CD4+ T-cell activation (Th1/Th17) and Treg suppression, transitioning from the early innate-driven systemic phase toward a chronic arthritis-dominant adaptive immune phase. Distinct clinical phenotypes reflect this: systemic disease correlates with higher IL-18 and IL-1β, while arthritis-driven disease shows elevated IL-6 and TNF-α.

This paper’s most clinically novel contribution is original multicenter data on IL-18 levels across the age spectrum. The authors analyzed 172 IL-18 measurements from sJIA and AOSD patients at three tertiary centers: Cincinnati Children’s Hospital, Hospital for Special Surgery (New York), and UMC Utrecht. Using Spearman’s rank correlation, they found:

This finding has important clinical implications. While IL-18 remains markedly elevated in both age groups compared to other inflammatory conditions — and is the most diagnostically informative biomarker for differentiating SD from sepsis, secondary HLH, malignancy-associated hyperinflammation, and other autoinflammatory diseases — absolute IL-18 thresholds validated in pediatric cohorts may not directly apply to adults.

IL-18 is best used as part of a multimarker framework alongside ferritin, IL-6, IFN-γ, and S100 proteins, not as a standalone diagnostic threshold.

Both sJIA and AOSD share peak genetic associations within the HLA class II region, confirming that adaptive immunity plays a role even in this prototypically autoinflammatory disease.

In sJIA: The landmark INCHARGE GWAS (902 patients, 8010 controls, 9 countries) identified HLA-DRB1*11 as the strongest genetic risk factor, within a 243 kb haplotype including HLA-DRA, the HLA-DRB cluster, HLA-DQA1, and HLA-DQB1. Critically, this genetic signature is distinct from other JIA subtypes, reinforcing sJIA as a biologically separate entity. A secondary signal involved IL1RN promoter variants linked to reduced IL-1Ra expression and, in some cohorts, to anakinra response, though cross-ancestry replication has been inconsistent.

In AOSD: The only published GWAS (264 Chinese patients) identified genome-wide significant associations at HLA-DRA/DRB5 and HLA-G, with the strongest MHC signal arising from HLA-DRB1*15:01, HLA-DQB1*06:02, and HLA-DQA1*01:02 — alleles distinct from those in sJIA.

The critical HLA-DRB1*15:01 divergence:

• In adults (AOSD): HLA-DRB1*15:01 confers susceptibility to Still’s itself.
• In children (sJIA): The same allele is instead linked to Stills-associated lung disease and hypersensitivity reactions to IL-1/IL-6 inhibitors (odds ratios >50), not to disease onset.

This allele-dependent age-specific functional divergence is one of the most clinically actionable genetic findings in SD. Beyond HLA, rare variants in HLH-related genes (UNC13D, STXBP2, PRF1) are enriched in SD and may predispose to MAS independent of disease onset. Some cases originally classified as SD were later reclassified as monogenic autoinflammatory diseases (mAIDs), emphasizing the need for genetic evaluation in atypical or refractory presentations.

(Editors note: there are more postulates than proof that HLA-DRB1*15;01 is associated with A) Still’s related lung disease [uncommon in kids, rare in adults]; or B) hypersensitivity reactions to either IL-1 or IL-6 inhibitor therapy that may antedate the few with lung disease.   HLA screening in my opinion is not standard but can be useful in research or on those with lung or hypersensitivity issues)

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