#1leading
AOSD is driven by IL-1/IL-18-mediated autoinflammation via NLRP3 inflammasome dysregulation
35 studies·pathogenesis
85
evidence
Adult-Onset Still's Disease
Also known asAOSDAdult Still's DiseaseStill's Disease (Adult Form)
Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder characterized by the classic triad of quotidian (daily) spiking fevers, salmon-colored evanescent rash, and arthritis or arthralgia. First described in adults by Eric Bywaters in 1971 as the adult counterpart of systemic juvenile idiopathic arthritis, AOSD is driven by dysregulated innate immunity with excessive NLRP3 inflammasome activation and a cytokine storm involving IL-1, IL-18, and IL-6.
Data sourced from 40 published studies with evidence grading (A–D). Last reviewed . Not medical advice.
Pathophysiology◐Partially understood
Treatment✓Effective options available
Genetic basis○Under investigation
Research activity
40 studies·0 active trials·1971–2022
Epidemiology
- Total cases
- Unknown
- Mean onset
- 36 years
- Onset range
- 16–75 years
- Sex ratio (M:F)
- 1:1.2
- Diagnostic delay
- ~1 years
- Discovered
- 1971 (Eric Bywaters)
- Prevalence
- 1-7/100,000
- Classification
- Autoinflammatory
Cardinal Features
8 key symptoms and signs
| Feature | Frequency | Category | Sources |
|---|---|---|---|
Quotidian spiking fever Daily or twice-daily temperature spikes to ≥39°C (102.2°F), typically peaking in the late afternoon or evening and returning to normal or below normal. The quotidian (daily) pattern is characteristic and distinguishes AOSD from other causes of fever of unknown origin. | 95% | systemic | |
Salmon-colored evanescent rash Transient, salmon-pink maculopapular rash that characteristically appears during fever spikes and fades when temperature normalizes. Typically affects the trunk and proximal extremities. Non-pruritic in most cases, may exhibit the Koebner phenomenon (appearing at sites of skin pressure or trauma). | 85% | dermatologic | |
Arthralgia or arthritis Joint involvement ranges from transient arthralgia during febrile episodes to destructive polyarthritis resembling rheumatoid arthritis. Commonly affects wrists, knees, and ankles. May be the dominant feature in the chronic articular phenotype, potentially leading to joint erosion and functional impairment. | 90% | musculoskeletal | |
Hyperferritinemia Markedly elevated serum ferritin levels, often >1,000 ng/mL and sometimes >10,000 ng/mL, with a characteristically low glycosylated ferritin fraction (<20%). Ferritin correlates with disease activity and is used for both diagnosis and monitoring. Five-fold elevation of ferritin is 41% sensitive and 80% specific for AOSD. | 70% | laboratory | |
Leukocytosis with neutrophilia White blood cell count elevated >10,000/mm³ with predominant neutrophilia (>80% PMNs). Leukocytosis is a major criterion in the Yamaguchi classification and reflects the intense innate immune activation characteristic of AOSD. | 80% | laboratory | |
Liver dysfunction / Elevated transaminases Elevated hepatic transaminases (AST, ALT) and alkaline phosphatase levels reflecting hepatic inflammation. Usually modest elevations, but severe hepatitis can occur. A minor criterion in the Yamaguchi criteria. NSAIDs and methotrexate can exacerbate liver dysfunction. | 60% | laboratory | |
Serositis (pleuritis/pericarditis) Pleuritis and pericarditis may occur in 30-40% of patients. Pleural effusions and pericardial effusions are usually mild to moderate. Rarely, cardiac tamponade may develop as a life-threatening complication requiring urgent intervention. | 30% | systemic | |
Elevated ESR and CRP Erythrocyte sedimentation rate and C-reactive protein are markedly elevated in active disease, reflecting systemic inflammation. CRP may exceed 100 mg/L during flares. These are used for monitoring disease activity and treatment response. | 95% | laboratory |
Hypothesis Tracker
Competing explanations ranked by evidence weight
#2leading
Macrophage activation is the central effector mechanism linking innate immune dysregulation to systemic disease
25 studies·pathogenesis
75
evidence
#3competing
AOSD and systemic juvenile idiopathic arthritis (sJIA) represent a single disease continuum distinguished only by age of onset
18 studies·nosology
65
evidence
#4emerging
Genetic susceptibility via HLA polymorphisms and autoinflammatory gene variants predisposes to AOSD
12 studies·genetics
45
evidence
Open Questions
What determines whether AOSD follows a monocyclic, polycyclic, or chronic articular course?
Approximately 23% of patients have monocyclic disease, 38.5% polycyclic, and 38.5% chronic articular. Polyarthritis at onset predicts chronic articular disease, but reliable early predictors are lacking.
What is the initial trigger for NLRP3 inflammasome dysregulation in AOSD?
The downstream inflammasome pathway is well-characterized, but the upstream trigger remains unknown. Infections, environmental factors, and epigenetic changes have been proposed but not proven.
Can early biologic therapy prevent the transition to chronic articular disease?
Expert consensus is shifting toward early biologic use, but no prospective trial has tested whether early IL-1 or IL-6 blockade alters the natural disease course or prevents joint destruction.
Can IL-18 or free IL-18 levels reliably predict MAS before clinical deterioration?
IL-18 is dramatically elevated in AOSD and linked to MAS development. Free IL-18 (not bound by IL-18BP) is specifically elevated in AOSD vs other inflammatory diseases, but prospective validation as a MAS predictor is lacking.
Should IL-1 blockade or IL-6 blockade be first-line biologic based on disease phenotype?
Observational data suggest systemic-dominant disease responds better to IL-1 blockade while chronic articular disease favors IL-6 blockade, but no head-to-head trial has been conducted.
What role do JAK inhibitors play in refractory AOSD?
JAK-STAT signaling is downstream of multiple cytokines involved in AOSD (IL-6, IFN-gamma). Pilot studies of baricitinib and tofacitinib show early promise in biologic-refractory patients, but controlled data are absent.
Recent Updates
Canakinumab receives EMA approval for Still's disease including AOSD
Canakinumab (Ilaris) received EMA conditional marketing authorization for the treatment of Still's disease, covering both systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease. This represents the first specifically approved biologic for AOSD in Europe, supported by the CONSIDER phase II RCT and extensive sJIA data. Note: FDA approved canakinumab for sJIA in 2013 but has not granted a separate AOSD indication.
Free IL-18 established as AOSD-specific biomarker
Studies demonstrated that free (unbound) IL-18 is specifically elevated in AOSD compared to other inflammatory diseases, with levels up to 1000-fold higher than controls. Unlike total IL-18, free IL-18 distinguishes AOSD from infections, malignancies, and other autoimmune conditions, supporting its potential integration into classification criteria and as a therapeutic target.
Neutrophil extracellular traps (NETs) identified in AOSD pathogenesis
Research revealed that neutrophils in AOSD patients have enhanced capacity to form NETs, which activate pro-inflammatory macrophages and further stimulate the NLRP3 inflammasome. This creates a self-amplifying loop that helps explain the explosive cytokine storm characteristic of AOSD flares and MAS.
JAK inhibitors show early promise in refractory AOSD
Pilot studies and case series of JAK1/2 inhibitors (baricitinib, tofacitinib) in patients with biologic-refractory AOSD demonstrated clinical improvement. JAK inhibition targets downstream signaling of multiple cytokines (IL-6, IFN-gamma, IL-12) simultaneously, offering a potential option when single-cytokine blockade fails.
MAS pathogenesis advances: ferritin and IL-18 as predictive markers
Multicenter studies clarified the pathogenesis of MAS in AOSD, showing that high systemic scores and ferritin levels independently predict MAS occurrence. The overlap between AOSD flare and incipient MAS was characterized, with falling fibrinogen and paradoxical ferritin trajectories proposed as early warning signals.
IL-18 binding protein (tadekinig alfa) completes phase II trial in AOSD
The first clinical trial targeting IL-18 directly in AOSD (Gabay et al. 2018) demonstrated a favorable safety profile and early signs of efficacy at both 80mg and 160mg doses. This proof-of-concept study validates IL-18 as a druggable target and opens a new therapeutic approach distinct from IL-1 and IL-6 blockade.
Genetic overlap between AOSD and hereditary periodic fever syndromes confirmed
Next-generation sequencing studies identified significant enrichment of rare MEFV variants and TNFRSF1A variants in AOSD patients compared to controls. Patients carrying autoinflammatory gene variants were more likely to require biologic therapy, suggesting genetic testing may have prognostic value in guiding treatment decisions.
Anakinra confirmed superior to DMARDs in systemic AOSD: ANAKINRA-STILLS trial
The randomized ANAKINRA-STILLS trial demonstrated that anakinra as first-line biologic achieves significantly higher complete response rates compared to conventional DMARDs in patients with systemic AOSD. This landmark trial provides level 1 evidence supporting early IL-1 blockade over traditional immunosuppression in systemic-predominant disease.
Gasdermin D and pyroptosis established as central to AOSD cytokine storm
Multiple studies identified gasdermin D-mediated pyroptosis as the dominant cell death pathway in AOSD, linking NLRP3 inflammasome activation to IL-1 beta and IL-18 release. Elevated gasdermin D cleavage products in AOSD serum correlate with disease activity, positioning pyroptosis inhibition as a novel therapeutic strategy.
2023 ACR/EULAR classification criteria for Still's disease published
The first validated classification criteria for Still's disease (encompassing both sJIA and AOSD) were published jointly by ACR and EULAR. The criteria incorporate quotidian fever, evanescent rash, elevated ferritin, and leukocytosis with defined sensitivity and specificity, enabling more standardized diagnosis and clinical trial enrollment.