| Domain | Feature / criterion | Typical AOSD characteristic | Frequency / quantitative detail | Diagnostic / clinical relevance | Key source |
|---|---|---|---|---|---|
| Major clinical manifestation | Fever | Daily high-spiking (quotidian) fever is a hallmark feature of AOSD | Included as a core defining feature in major reviews; fever is described as a characteristic manifestation across reviews | Central to classification and initial clinical suspicion; part of Yamaguchi major criteria | Tomaras et al., 2021, J Clin Med, doi:10.3390/jcm10040733; Macovei et al., 2022, Int J Mol Sci, doi:10.3390/ijms232112810 |
| Major clinical manifestation | Rash | Evanescent, salmon-pink rash, often accompanying fever spikes | Reported as one of the classic manifestations across reviews; skin rash present in 75% of the 24-patient NGS cohort | Supports diagnosis; can help distinguish systemic phenotype; atypical persistent eruptions have been linked to distinct inflammatory pathways | Tomaras et al., 2021, doi:10.3390/jcm10040733; Rao et al., 2022, doi:10.3389/fmed.2022.881431; Prieto-Peña et al., 2024, doi:10.3389/fimmu.2024.1474271 |
| Major clinical manifestation | Arthritis / arthralgia | Arthralgia or arthritis is common; chronic articular disease represents one major phenotype | In the Spanish NGS cohort, articular manifestations occurred in 91.7% (22/24) | Helps phenotype patients into systemic-predominant vs chronic articular disease course; included in Yamaguchi major criteria (arthralgia/arthritis) | Tomaras et al., 2021, doi:10.3390/jcm10040733; Prieto-Peña et al., 2024, doi:10.3389/fimmu.2024.1474271 |
| Major clinical manifestation | Sore throat | Prominent early symptom frequently noted in AOSD | Reported as a characteristic manifestation in reviews | Useful supportive clue in differential diagnosis; included in Fautrel criteria as pharyngitis | Tsuboi et al., 2022, doi:10.3389/fimmu.2022.953730; Macovei et al., 2022, doi:10.3390/ijms232112810 |
| Other common systemic manifestations | Lymphadenopathy / hepatosplenomegaly | Multisystem inflammatory involvement commonly includes lymphadenopathy and hepatosplenomegaly/splenomegaly | Qualitatively frequent in reviews; lymphadenopathy specifically highlighted in pathogenesis and clinical reviews | Important in differential diagnosis because infection and malignancy must be excluded | Tsuboi et al., 2022, doi:10.3389/fimmu.2022.953730; Rao et al., 2022, doi:10.3389/fmed.2022.881431 |
| Laboratory finding | Hyperferritinemia | Markedly elevated ferritin is a hallmark laboratory abnormality | Five-fold higher ferritin in active AOSD than severe COVID-19 in one cross-sectional study; ferritin correlates with inflammatory activity in multiple studies | High value for diagnosis, disease activity assessment, and concern for MAS; incorporated into Fautrel approach with glycosylated ferritin | Tomaras et al., 2021, doi:10.3390/jcm10040733; Chen et al., 2021, doi:10.3389/fimmu.2021.719544; Jia et al., 2022, doi:10.1038/s41467-022-34560-7 |
| Laboratory finding | IL-18 elevation | IL-18 is one of the most distinctive cytokine abnormalities in AOSD | ROC AUC 0.91 with cutoff 18,550 pg/mL for distinguishing AOSD ± MAS from adult secondary HLH; in another study AUC 0.948 with cutoff 190.5 pg/mL for distinguishing active AOSD from severe COVID-19; active AOSD showed 68-fold higher IL-18 than severe COVID-19 | Strong candidate biomarker for diagnosis, differential diagnosis, and disease monitoring; biologically linked to inflammasome activation and MAS risk | Shiga et al., 2021, doi:10.3389/fimmu.2021.750114; Chen et al., 2021, doi:10.3389/fimmu.2021.719544; Baggio et al., 2023, doi:10.3390/ijms241311125 |
| Laboratory finding | Leukocytosis / neutrophilia | Leukocytosis with neutrophil predominance is characteristic | In the U.S. claims cohort, leukocytosis was part of the characteristic case profile; reviews consistently describe increased leukocyte counts and neutrophil percentage | Included in Yamaguchi major criteria and often helps distinguish AOSD from mimics when paired with negative ANA/RF and hyperferritinemia | Ma et al., 2021, doi:10.1093/rheumatology/keab485; Rao et al., 2022, doi:10.3389/fmed.2022.881431; Lenert et al., 2020, doi:10.1093/rheumatology/kez622 |
| Laboratory finding | Elevated ESR / CRP | Acute-phase reactants are usually markedly elevated in active disease | All 24 patients in the Spanish NGS cohort had elevated acute-phase reactants; reviews consistently report high ESR and CRP | Useful for activity assessment, though nonspecific; very high inflammatory markers may raise concern for severe systemic disease or impending MAS | Rao et al., 2022, doi:10.3389/fmed.2022.881431; Prieto-Peña et al., 2024, doi:10.3389/fimmu.2024.1474271 |
| Serology / exclusionary tests | ANA / RF negativity | Autoantibody tests are usually negative | Reported qualitatively across reviews | Supports the autoinflammatory rather than classic autoimmune profile; relevant to Yamaguchi exclusion framework | Rao et al., 2022, doi:10.3389/fmed.2022.881431; Galozzi et al., 2022, doi:10.2147/BTT.S290329 |
| Diagnostic criteria | Yamaguchi criteria | Most widely used classification criteria; based on major and minor clinical/laboratory features with exclusion of infection, malignancy, and other rheumatic diseases | In the U.S. claims study, 35.9% of coded AOSD cases fulfilled claims-based Yamaguchi criteria vs 0.4% of controls | Remains the most commonly used criteria set in practice and research | Macovei et al., 2022, doi:10.3390/ijms232112810; Lenert et al., 2020, doi:10.1093/rheumatology/kez622 |
| Diagnostic criteria | Fautrel criteria | Alternative validated criteria set incorporating ferritin and glycosylated ferritin, without mandatory exclusion variables | Qualitatively described as advantageous because they add ferritin/glycosylated ferritin values | Often considered useful when ferritin biology is prominent and to improve specificity | Macovei et al., 2022, doi:10.3390/ijms232112810 |
| Disease phenotype | Systemic phenotype | Predominantly systemic inflammatory presentation with fever, rash, high ferritin, organ involvement, cytokine storm features | Contemporary reviews increasingly group AOSD into two broad phenotypes | More likely to align with IL-1/IL-18-driven hyperinflammation and risk of severe complications such as MAS | Tomaras et al., 2021, doi:10.3390/jcm10040733; Bindoli et al., 2024, doi:10.1007/s40265-024-01993-x |
| Disease phenotype | Chronic articular phenotype | Persistent arthritis-dominant course with less prominent systemic flares over time | Contemporary reviews describe this as the second major phenotype | Guides treatment selection and prognosis, often prompting DMARD/biologic strategies aimed at articular control | Tomaras et al., 2021, doi:10.3390/jcm10040733; Macovei et al., 2022, doi:10.3390/ijms232112810 |
| Disease course pattern | Monophasic / polycyclic / chronic articular | Three classic courses: self-limited monophasic, intermittent/polycyclic systemic, and chronic articular | Qualitative classification widely cited in reviews | Important for prognosis and long-term management planning | Macovei et al., 2022, doi:10.3390/ijms232112810 |
| Major complication | Macrophage activation syndrome (MAS) / secondary HLH | Severe life-threatening hyperinflammatory complication with immune overactivation and organ damage | 4.7% MAS in the U.S. claims cohort; in a meta-analysis of biologic-treated cohorts, pooled MAS incidence was 1.50% with anakinra-treated patients and 14.01% with tocilizumab-treated patients, though confounding by indication is likely | Requires urgent recognition; ferritin surge, cytopenias or organ-damage markers, and extreme cytokine activation are red flags | Tomaras et al., 2021, doi:10.3390/jcm10040733; Lenert et al., 2020, doi:10.1093/rheumatology/kez622; Adachi et al., 2023, doi:10.1007/s40744-023-00600-x |
| MAS-associated biomarkers | Ferritin, sIL-2R, CXCL10, IL-18 | Biomarker pattern of MAS includes very high ferritin and IL-18; emerging evidence supports CXCL10 and intermediate monocytes | IL-18, sIL-2R, and arthralgia/arthritis independently differentiated AOSD from adult HLH; plasma CXCL10 identified as a potential biomarker for AOSD-MAS | Useful for differential diagnosis and early recognition of MAS in severe systemic disease | Shiga et al., 2021, doi:10.3389/fimmu.2021.750114; Jia et al., 2023, doi:10.1186/s12916-023-03231-9 |
| Mechanistically relevant laboratory/immunology | NETs / monocyte-macrophage activation | NET formation, intermediate monocyte expansion, inflammasome activation, and cytokine storm are key disease features | Active AOSD and AOSD-MAS show higher intermediate monocyte proportions and elevated IL-1β, IL-6, CCL8, CXCL10 | Helps explain transition from systemic inflammation to MAS and supports biomarker- and pathway-directed therapy | Tsuboi et al., 2022, doi:10.3389/fimmu.2022.953730; Jia et al., 2023, doi:10.1186/s12916-023-03231-9; Jia et al., 2022, doi:10.1038/s41467-022-34560-7 |


*Table: This table summarizes the core clinical manifestations, laboratory findings, diagnostic criteria, phenotypic patterns, and major complications of adult-onset Still disease using the retrieved literature. It is useful as a compact reference for disease recognition, differential diagnosis, and knowledge base curation.*