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Ostermayer: Created page with "==Background== Adult-onset Still's disease (AOSD) is a rare systemic '''autoinflammatory''' disorder characterized by quotidian fevers, evanescent rash, and arthritis/arthralgiaEfthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65(5):564-72. Now recognized as the adult counterpart of systemic juvenile idiopathic arthritis (sJIA); together they fo..."

2026-03-09T19:23:48Z

Created page with "==Background== *Adult-onset Still's disease (AOSD) is a rare systemic '''autoinflammatory''' disorder characterized by quotidian fevers, evanescent rash, and arthritis/arthralgia<ref name="Efthimiou2006">Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65(5):564-72.</ref> *Now recognized as the adult counterpart of systemic juvenile idiopathic arthritis (sJIA); together they fo..."

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==Background==
*Adult-onset Still's disease (AOSD) is a rare systemic '''autoinflammatory''' disorder characterized by quotidian fevers, evanescent rash, and arthritis/arthralgia<ref name="Efthimiou2006">Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65(5):564-72.</ref>
*Now recognized as the adult counterpart of [[Juvenile idiopathic arthritis|systemic juvenile idiopathic arthritis (sJIA)]]; together they form the '''Still's disease''' spectrum<ref name="EULAR2024">Fautrel B, Mitrovic S, De Matteis A, et al. EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease. Ann Rheum Dis. 2024;83(12):1614-27.</ref>
*Driven by innate immune system dysregulation with elevated IL-1, IL-6, and IL-18
*Accounts for 5-10% of cases of [[fever of unknown origin]] in adults<ref name="PMCreview">Kadavath S, Efthimiou P. Adult onset Still's disease: A Review on Diagnostic Workup and Treatment Options. Open Rheumatol J. 2015;9:23-8.</ref>
*'''Diagnosis of exclusion''' — infection and malignancy must be ruled out first
*Bimodal age distribution with peaks at 15-25 years and 36-46 years; slight female predominance<ref name="Efthimiou2006"/>
*Incidence: ~0.16-0.4 per 100,000 per year
*Three clinical courses:<ref name="Efthimiou2006"/>
**'''Monocyclic''' (~30%): single episode resolving within 1 year
**'''Polycyclic/intermittent''' (~30%): recurrent flares separated by periods of remission
**'''Chronic articular''' (~40%): persistent destructive polyarthritis — worst long-term prognosis

==Clinical Features==
===Classic Triad===
#'''Quotidian (daily spiking) fever'''
#'''Evanescent salmon-colored rash'''
#'''Arthralgia or arthritis'''

===Fever===
*High spiking fevers ≥39°C (102.2°F), typically 1-2 spikes per day (quotidian or double-quotidian pattern)
*Characteristically spikes in the '''late afternoon/evening''' then returns to normal or '''below normal''' baseline
*Patient may appear '''toxic during spikes''' and '''remarkably well''' between them
*Must be present for ≥1 week to meet Yamaguchi criteria
*'''ED Pearl:''' Change from intermittent spiking to '''continuous high fever''' should raise concern for [[macrophage activation syndrome]] (MAS)

===Rash===
*'''Evanescent''' (appears and disappears with fever spikes), salmon-pink, macular or maculopapular
*Trunk, proximal extremities; typically spares the face
*Non-pruritic (though a subset of patients may report pruritus), non-scarring
*May be provoked by skin scratching or pressure ('''Koebner phenomenon''')
*'''ED Pearl:''' Rash may be absent when the patient is afebrile in the ED — ask the patient to show photos from home, or examine during a fever spike

===Musculoskeletal===
*Arthralgia and/or arthritis, often polyarticular
*Wrists, knees, and ankles most commonly affected
*Arthralgia must be present for ≥2 weeks to meet Yamaguchi criteria
*In the chronic articular pattern, can progress to destructive joint disease

===Other Features===
*'''Sore throat''' (70%) — often the initial complaint; may be mistaken for pharyngitis; cultures are negative
*'''[[Lymphadenopathy]]''' (50%)
*'''[[Hepatomegaly]] and/or [[splenomegaly]]''' (50%)
*'''Serositis:''' [[pericarditis]], [[pericardial effusion]], [[pleural effusion]], peritonitis
*'''[[Myalgia]]''' — can be severe
*'''Weight loss'''
*'''Abdominal pain'''
*Rare: [[myocarditis]], [[ARDS]], aseptic [[meningitis]], [[DIC]], fulminant hepatitis

===Macrophage Activation Syndrome (MAS)===
*The most life-threatening complication of AOSD; occurs in ~12-17% of patients<ref name="Efthimiou2006"/>
*See [[Macrophage activation syndrome]] for full details
*Suspect if: continuous fever, falling platelets, falling ESR, markedly rising ferritin, falling fibrinogen, transaminitis, hemorrhagic manifestations, encephalopathy

==Differential Diagnosis==
''AOSD is a diagnosis of exclusion. The following must be considered and excluded before making the diagnosis:''

===Infections===
*[[Endocarditis]]
*[[EBV]], [[CMV]], parvovirus B19, [[HIV]], [[hepatitis B]], [[hepatitis C]]
*[[Tuberculosis]]
*[[Lyme disease]]
*Occult [[abscess]]
*[[COVID-19]]

===Malignancy===
*[[Lymphoma]] (especially T-cell) — most important mimicker
*[[Leukemia]]
*Castleman disease
*Solid organ tumors with paraneoplastic features

===Autoimmune/Inflammatory===
*[[Systemic lupus erythematosus]]
*[[Reactive arthritis]]
*[[Polyarteritis nodosa]] and other vasculitides
*[[Rheumatoid arthritis]] (typically RF+)
*[[Sarcoidosis]]
*[[Inflammatory bowel disease]]
*[[Familial Mediterranean fever]] and other hereditary periodic fever syndromes
*[[Schnitzler syndrome]] (urticarial rash + monoclonal gammopathy)

===Other===
*Drug reaction (including [[DRESS syndrome]])
*[[Thyroiditis]]
*[[Sweet syndrome]] (acute febrile neutrophilic dermatosis)

{{Fever of unknown origin DDX}}

==Evaluation==
===Workup===
;Hematology:
*'''CBC with differential:''' leukocytosis (often >15,000/µL) with '''≥80% granulocytes''' (neutrophilia) is a hallmark; anemia of chronic disease; thrombocytosis
**'''Falling''' platelets or WBC should raise concern for MAS
*'''Peripheral blood smear:''' to exclude blasts ([[leukemia]], [[lymphoma]])

;Inflammatory Markers:
*'''[[Ferritin]]:''' markedly elevated (often >1,000 ng/mL; may exceed 10,000 ng/mL)
**'''Glycosylated ferritin fraction ≤20%''' is highly suggestive of AOSD (normally ~50-80%); sensitivity ~70%, specificity ~80%<ref name="Fautrel2001">Fautrel B, Le Moël G, Saint-Marcoux B, et al. Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease. J Rheumatol. 2001;28(2):322-9.</ref>
**Ferritin >5× normal is uncommon outside of AOSD, MAS/HLH, hemochromatosis, and hepatocellular injury
*'''ESR, [[CRP]]:''' markedly elevated
*'''Paradoxical ESR drop''' with rising CRP suggests MAS (fibrinogen consumption)

;Hepatic:
*'''AST/ALT:''' frequently elevated (transaminitis in 50-75% of cases)
*'''LDH:''' elevated
*'''Bilirubin, albumin'''

;Coagulation:
*'''Fibrinogen:''' elevated in active AOSD (acute phase reactant); '''falling fibrinogen''' suggests MAS
*'''D-dimer, PT/PTT:''' assess for DIC if MAS suspected

;Serology (to exclude mimickers):
*'''ANA:''' typically '''negative''' (positive in <10%; if strongly positive → consider SLE)
*'''RF:''' typically '''negative''' (positive in <10%; if positive → consider RA)
*'''Anti-CCP:''' negative
*If ANA and RF are positive, the diagnosis of AOSD is much less likely

;Infection Workup:
*'''Blood cultures''' (×2 sets, mandatory)
*'''Procalcitonin''' (may help differentiate from sepsis, though can be mildly elevated in AOSD)
*Viral serologies: [[EBV]], [[CMV]], [[HIV]], [[hepatitis B]], [[hepatitis C]], parvovirus B19
*'''Throat culture''' (to exclude infectious pharyngitis)
*'''Urinalysis and urine culture'''

;Imaging:
*'''[[CXR]]:''' evaluate for [[pleural effusion]], infiltrate, [[lymphadenopathy]]
*'''[[CT chest/abdomen/pelvis]]''' or '''PET/CT:''' to evaluate for lymphadenopathy and occult malignancy; recommended before starting corticosteroids<ref name="EULAR2024"/>
*'''[[Echocardiography]]:''' if concern for [[pericardial effusion]] or [[myocarditis]]
*'''Joint imaging:''' [[ultrasound]] or radiographs of involved joints

;Additional Considerations:
*'''sIL-2R (soluble CD25), IL-18:''' if available, may support the diagnosis; should ideally be obtained before starting corticosteroids<ref name="EULAR2024"/>
*'''Bone marrow biopsy:''' consider if [[lymphoma]], [[leukemia]], or MAS is on the differential
*'''Lymph node biopsy:''' if significant adenopathy — to exclude lymphoma

===Diagnosis===
''AOSD is a clinical diagnosis of exclusion. The Yamaguchi criteria are the most widely used and most sensitive (93.5%).''<ref name="Yamaguchi1992">Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19(3):424-30.</ref>

====Yamaguchi Criteria====
Requires '''≥5 criteria''' with '''at least 2 major:'''

;Major Criteria:
#Fever ≥39°C (102.2°F) lasting ≥1 week
#Arthralgia or arthritis lasting ≥2 weeks
#Nonpruritic, salmon-colored, macular or maculopapular rash (usually on trunk/extremities during febrile episodes)
#Leukocytosis ≥10,000/µL with ≥80% granulocytes

;Minor Criteria:
#Sore throat
#Lymphadenopathy and/or splenomegaly
#Hepatomegaly or abnormal liver function tests (elevated AST, ALT, or LDH)
#Negative ANA and negative RF

;Exclusion Criteria (must be ruled out):
*Infections (especially sepsis and EBV)
*Malignancy (especially lymphoma)
*Other autoimmune diseases (especially SLE and systemic vasculitis)

====Fautrel Criteria====
An alternative set that incorporates ferritin and glycosylated ferritin (sensitivity 81%, specificity 98.5%):<ref name="Fautrel2002">Fautrel B, Zing E, Golmard JL, et al. Proposal for a new set of classification criteria for adult-onset still disease. Medicine (Baltimore). 2002;81(3):194-200.</ref>

;Major: Spiking fever ≥39°C; arthralgia; transient erythema; pharyngitis; PMN ≥80%; glycosylated ferritin ≤20%
;Minor: Maculopapular rash; leukocytosis ≥10,000/µL
;Requires: ≥4 major, or 3 major + 2 minor

====ED Diagnostic Pearls====
*A '''massively elevated ferritin''' (>1,000 ng/mL) with '''negative ANA and RF''' in a young adult with quotidian fevers, rash, and sore throat is AOSD until proven otherwise
*'''Ferritin >5× upper limit of normal''' has a limited differential: AOSD, MAS/HLH, hemochromatosis, hepatocellular injury, and rarely renal failure
*The '''glycosylated ferritin fraction ≤20%''' (if available) adds specificity
*Do '''not''' anchor on a diagnosis of AOSD until infection and lymphoma have been adequately excluded — these patients often undergo extensive workups over days to weeks

==Management==
''Management in the ED focuses on stabilization, exclusion of mimickers, and initiation of anti-inflammatory therapy in consultation with rheumatology.''

===Acute ED Management===
*'''Hemodynamic stabilization''' if MAS or sepsis is suspected
*'''Empiric [[antibiotics]]''' if infection has not been excluded — these patients frequently appear septic
*'''Antipyretics''' for symptom control
*'''[[NSAIDs]]''' for mild disease (arthralgia, fever, mild serositis):
**[[Naproxen]] 250-500 mg BID, [[ibuprofen]] 400-800 mg TID, or [[indomethacin]] 25-50 mg TID
**NSAIDs alone are effective in only ~20% of patients<ref name="Efthimiou2006"/>
*'''[[Corticosteroids]]''' for moderate-severe disease (after infection/malignancy excluded):
**[[Prednisone]] 0.5-1 mg/kg/day PO (most common initial regimen)
**IV [[methylprednisolone]] 1g/day pulse ×3 days for severe systemic disease, serositis, or MAS
**Effective in ~60% of patients; however, steroid dependence and toxicity are common<ref name="Efthimiou2006"/>
**'''Do not start steroids before adequate workup to exclude lymphoma''' — steroids can mask lymphoma for weeks to months

===Definitive Therapy (Rheumatology-Directed)===
*'''IL-1 inhibitors''' are increasingly considered '''first-line''' alongside or instead of steroids, especially for the systemic inflammatory phenotype:<ref name="EULAR2024"/>
**'''[[Anakinra]]''' (IL-1 receptor antagonist): 100 mg SC daily; rapid onset
**'''Canakinumab''' (anti-IL-1β monoclonal antibody): FDA-approved for AOSD (2020); 4 mg/kg SC q4 weeks
*'''IL-6 inhibitors:'''
**'''[[Tocilizumab]]''' (anti-IL-6 receptor): effective for both systemic and articular manifestations; 8 mg/kg IV q4 weeks or 162 mg SC weekly
*'''DMARDs''' (steroid-sparing):
**'''[[Methotrexate]]''' 10-25 mg PO/SC weekly (most commonly used conventional DMARD for AOSD)
*'''Avoid anti-TNF agents''' — generally less effective in AOSD and may trigger MAS<ref name="Efthimiou2006"/>

===If MAS Suspected===
*See [[Macrophage activation syndrome]]
*Emergent rheumatology and/or hematology consultation
*High-dose IV [[methylprednisolone]] (30 mg/kg, max 1g)
*[[Anakinra]] at higher doses (2-10 mg/kg/day)
*[[Cyclosporine A]]
*Do '''not''' delay treatment while awaiting bone marrow biopsy results

===Consultations===
*'''Rheumatology:''' All patients with suspected AOSD
*'''Hematology/oncology:''' If lymphoma or MAS is on the differential
*'''Infectious disease:''' If atypical infection is being considered
*'''Cardiology:''' If significant [[pericardial effusion]] or [[myocarditis]]

==Disposition==
*'''Admit''' nearly all patients with suspected new-onset AOSD for:
**Completion of infectious and malignancy workup
**Observation for MAS (can develop at any time)
**Initiation and monitoring of immunosuppressive therapy
**Rheumatology consultation
*'''ICU admission''' if:
**MAS with hemodynamic instability, coagulopathy, or multi-organ dysfunction
**Hemodynamic compromise from [[pericardial effusion]]
**[[ARDS]] or respiratory failure
**Fulminant hepatitis
*'''Consider ED discharge with urgent rheumatology follow-up (24-72h)''' only if:
**Mild disease (isolated fever, arthralgia, no serositis)
**Infection and malignancy have been adequately excluded
**Hemodynamically stable, no evidence of MAS
**Reliable follow-up confirmed
**Clear return precautions given (worsening fever, bleeding, confusion, new symptoms)

==See Also==
*[[Systemic JIA]]
*[[Macrophage activation syndrome]]
*[[Hemophagocytic lymphohistiocytosis]]
*[[Fever of unknown origin]]
*[[Pericardial effusion and tamponade]]
*[[Sepsis (Main)]]

==External Links==
*[https://www.mdcalc.com/calc/10095/yamaguchi-criteria-adult-onset-stills-disease-aosd MDCalc - Yamaguchi Criteria for AOSD]
*[https://www.mdcalc.com/calc/4053/hscore-reactive-hemophagocytic-syndrome MDCalc - HScore (for MAS/HLH screening)]
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC1798146/ PMC - Diagnosis and Management of AOSD (Review)]
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC4794578/ PMC - AOSD: Diagnostic Workup and Treatment Options]

==References==
{{reflist|2}}

[[Category:Rheumatology]]
[[Category:ID]]

Adult-onset Still's disease - Revision history

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