Adult-onset Still's disease

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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