Ver el código de «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<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]]