Adult-onset Still's disease: Difference between revisions

(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==
==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>
*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>
*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
*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>
*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>
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*Incidence: ~0.16-0.4 per 100,000 per year
*Incidence: ~0.16-0.4 per 100,000 per year
*Three clinical courses:<ref name="Efthimiou2006"/>
*Three clinical courses:<ref name="Efthimiou2006"/>
**'''Monocyclic''' (~30%): single episode resolving within 1 year
**Monocyclic (~30%): single episode resolving within 1 year
**'''Polycyclic/intermittent''' (~30%): recurrent flares separated by periods of remission
**Polycyclic/intermittent (~30%): recurrent flares separated by periods of remission
**'''Chronic articular''' (~40%): persistent destructive polyarthritis — worst long-term prognosis
**Chronic articular (~40%): persistent destructive polyarthritis — worst long-term prognosis


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


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


===Rash===
===Rash===
*'''Evanescent''' (appears and disappears with fever spikes), salmon-pink, macular or maculopapular
*Evanescent (appears and disappears with fever spikes), salmon-pink, macular or maculopapular
*Trunk, proximal extremities; typically spares the face
*Trunk, proximal extremities; typically spares the face
*Non-pruritic (though a subset of patients may report pruritus), non-scarring
*Non-pruritic (though a subset of patients may report pruritus), non-scarring
*May be provoked by skin scratching or pressure ('''Koebner phenomenon''')
*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
*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===
===Musculoskeletal===
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===Other Features===
===Other Features===
*'''Sore throat''' (70%) — often the initial complaint; may be mistaken for pharyngitis; cultures are negative
*Sore throat (70%) — often the initial complaint; may be mistaken for pharyngitis; cultures are negative
*'''[[Lymphadenopathy]]''' (50%)
*[[Lymphadenopathy]] (50%)
*'''[[Hepatomegaly]] and/or [[splenomegaly]]''' (50%)
*[[Hepatomegaly]] and/or [[splenomegaly]] (50%)
*'''Serositis:''' [[pericarditis]], [[pericardial effusion]], [[pleural effusion]], peritonitis
*Serositis: [[pericarditis]], [[pericardial effusion]], [[pleural effusion]], peritonitis
*'''[[Myalgia]]''' — can be severe
*[[Myalgia]] — can be severe
*'''Weight loss'''
*Weight loss
*'''Abdominal pain'''
*Abdominal pain
*Rare: [[myocarditis]], [[ARDS]], aseptic [[meningitis]], [[DIC]], fulminant hepatitis
*Rare: [[myocarditis]], [[ARDS]], aseptic [[meningitis]], [[DIC]], fulminant hepatitis


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


;Inflammatory Markers:
;Inflammatory Markers:
*'''[[Ferritin]]:''' markedly elevated (often >1,000 ng/mL; may exceed 10,000 ng/mL)
*[[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>
**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
**Ferritin >5× normal is uncommon outside of AOSD, MAS/HLH, hemochromatosis, and hepatocellular injury
*'''ESR, [[CRP]]:''' markedly elevated
*ESR, [[CRP]]: markedly elevated
*'''Paradoxical ESR drop''' with rising CRP suggests MAS (fibrinogen consumption)
*Paradoxical ESR drop with rising CRP suggests MAS (fibrinogen consumption)


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


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


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


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


;Imaging:
;Imaging:
*'''[[CXR]]:''' evaluate for [[pleural effusion]], infiltrate, [[lymphadenopathy]]
*[[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"/>
*[[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]]
*[[Echocardiography]]: if concern for [[pericardial effusion]] or [[myocarditis]]
*'''Joint imaging:''' [[ultrasound]] or radiographs of involved joints
*Joint imaging: [[ultrasound]] or radiographs of involved joints


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


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


;Major Criteria:
;Major Criteria:
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====ED Diagnostic Pearls====
====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
*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
*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
*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
*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==
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===Acute ED Management===
===Acute ED Management===
*'''Hemodynamic stabilization''' if MAS or sepsis is suspected
*Hemodynamic stabilization if MAS or sepsis is suspected
*'''Empiric [[antibiotics]]''' if infection has not been excluded — these patients frequently appear septic
*Empiric [[antibiotics]] if infection has not been excluded — these patients frequently appear septic
*'''Antipyretics''' for symptom control
*Antipyretics for symptom control
*'''[[NSAIDs]]''' for mild disease (arthralgia, fever, mild serositis):
*[[NSAIDs]] for mild disease (arthralgia, fever, mild serositis):
**[[Naproxen]] 250-500 mg BID, [[ibuprofen]] 400-800 mg TID, or [[indomethacin]] 25-50 mg TID
**[[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"/>
**NSAIDs alone are effective in only ~20% of patients<ref name="Efthimiou2006"/>
*'''[[Corticosteroids]]''' for moderate-severe disease (after infection/malignancy excluded):
*[[Corticosteroids]] for moderate-severe disease (after infection/malignancy excluded):
**[[Prednisone]] 0.5-1 mg/kg/day PO (most common initial regimen)
**[[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
**IV [[methylprednisolone]] 1g/day pulse ×3 days for severe systemic disease, serositis, or MAS
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===Definitive Therapy (Rheumatology-Directed)===
===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"/>
*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
**[[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
**Canakinumab (anti-IL-1β monoclonal antibody): FDA-approved for AOSD (2020); 4 mg/kg SC q4 weeks
*'''IL-6 inhibitors:'''
*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
**'''[[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):
*DMARDs (steroid-sparing):
**'''[[Methotrexate]]''' 10-25 mg PO/SC weekly (most commonly used conventional DMARD for AOSD)
**[[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"/>
*Avoid anti-TNF agents — generally less effective in AOSD and may trigger MAS<ref name="Efthimiou2006"/>


===If MAS Suspected===
===If MAS Suspected===
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*[[Anakinra]] at higher doses (2-10 mg/kg/day)
*[[Anakinra]] at higher doses (2-10 mg/kg/day)
*[[Cyclosporine A]]
*[[Cyclosporine A]]
*Do '''not''' delay treatment while awaiting bone marrow biopsy results
*Do not delay treatment while awaiting bone marrow biopsy results


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


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

Latest revision as of 09:37, 22 March 2026

Background

  • Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder characterized by quotidian fevers, evanescent rash, and arthritis/arthralgia[1]
  • Now recognized as the adult counterpart of systemic juvenile idiopathic arthritis (sJIA); together they form the Still's disease spectrum[2]
  • 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[3]
  • 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[1]
  • Incidence: ~0.16-0.4 per 100,000 per year
  • Three clinical courses:[1]
    • 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

  1. Quotidian (daily spiking) fever
  2. Evanescent salmon-colored rash
  3. 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

Macrophage Activation Syndrome (MAS)

  • The most life-threatening complication of AOSD; occurs in ~12-17% of patients[1]
  • 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

Malignancy

  • Lymphoma (especially T-cell) — most important mimicker
  • Leukemia
  • Castleman disease
  • Solid organ tumors with paraneoplastic features

Autoimmune/Inflammatory

Other

Infections (~30%)

Malignancy (~20%)

  • Hematologic (most common malignant cause of FUO)
    • Lymphoma (Hodgkin and non-Hodgkin)
    • Leukemia (especially acute leukemia)
    • Multiple myeloma
    • Myelodysplastic syndrome
    • Castleman disease
  • Solid Tumors
    • Renal cell carcinoma
    • Hepatocellular carcinoma
    • Colon cancer
    • Pancreatic cancer
    • Atrial myxoma
    • Pheochromocytoma

Autoimmune/Inflammatory (~20%)

Drug Fever

Endocrine/Metabolic

Thromboembolic/Vascular

Factitious/Habitual

  • Factitious fever (self-induced)
  • Munchausen syndrome / Munchausen by proxy (pediatric)

Miscellaneous

  • Post-surgical/post-procedural inflammation
  • Gout/pseudogout (crystal arthropathy)
  • Cirrhosis / alcoholic hepatitis
  • Hemolytic anemia
  • Transfusion reaction
  • Tissue necrosis (rhabdomyolysis, large hematoma, pancreatitis)
  • Hypothalamic dysfunction (central fever)
  • Periodic fever of unknown cause (~10-15% of FUO never diagnosed)

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%[4]
    • 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
Additional Considerations
  • sIL-2R (soluble CD25), IL-18: if available, may support the diagnosis; should ideally be obtained before starting corticosteroids[2]
  • 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%).[5]

Yamaguchi Criteria

Requires ≥5 criteria with at least 2 major:

Major Criteria
  1. Fever ≥39°C (102.2°F) lasting ≥1 week
  2. Arthralgia or arthritis lasting ≥2 weeks
  3. Nonpruritic, salmon-colored, macular or maculopapular rash (usually on trunk/extremities during febrile episodes)
  4. Leukocytosis ≥10,000/µL with ≥80% granulocytes
Minor Criteria
  1. Sore throat
  2. Lymphadenopathy and/or splenomegaly
  3. Hepatomegaly or abnormal liver function tests (elevated AST, ALT, or LDH)
  4. 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%):[6]

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):
  • 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[1]
    • 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:[2]
    • 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[1]

If MAS Suspected

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

External Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65(5):564-72.
  2. ↑ 2.0 2.1 2.2 2.3 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.
  3. ↑ Kadavath S, Efthimiou P. Adult onset Still's disease: A Review on Diagnostic Workup and Treatment Options. Open Rheumatol J. 2015;9:23-8.
  4. ↑ 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.
  5. ↑ Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19(3):424-30.
  6. ↑ 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.
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