Adult-onset Still disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Adult-onset Still disease is a rare systemic autoinflammatory disorder. Establish fever timing, rash relation, sore throat, joint symptoms, weight loss, lymph nodes, travel, infection exposure, medicines and malignancy symptoms. Examine during fever if possible and assess joints, skin, liver, spleen, nodes, heart, lungs and neurological state. Classification criteria can structure evidence but do not replace exclusion of dangerous mimics.

Initial tests often show neutrophilic leucocytosis, very high CRP and ESR, anaemia, thrombocytosis and raised liver enzymes. Ferritin may be strikingly raised; glycosylated ferritin is not universally available and no ferritin threshold is diagnostic. RF and ANA help evaluate alternatives. Blood cultures, viral and tuberculosis testing, echocardiography, cross-sectional imaging and tissue or marrow sampling are selected from the phenotype.

Macrophage activation syndrome can emerge at presentation or during treatment. Look for a change from inflammatory thrombocytosis to falling platelets, cytopenias, falling fibrinogen, rising triglycerides, coagulopathy, hepatitis, encephalopathy and shock. Ferritin trajectory can support urgency. Infection, malignancy-associated HLH and drug reaction remain parallel possibilities; urgent treatment should be coordinated before every criterion is fulfilled.

Treatment is specialist-led. Current EULAR/PReS recommendations prioritise early IL-1 or IL-6 inhibition once the diagnosis is established, aiming for inactive disease while avoiding prolonged systemic glucocorticoids. Short glucocorticoid treatment can bridge targeted therapy or control severe organ disease; methotrexate may support a chronic arthritis-dominant phenotype. Monitor infection, neutropenia, liver tests, lipids and agent-specific reproductive or vaccine risks.

Key points

Adult-onset Still disease is a diagnosis of pattern and exclusion: high spiking fever, evanescent salmon-pink rash, inflammatory arthritis, neutrophilia, sore throat, lymphadenopathy and liver inflammation are typical clues.
Rash may appear with fever and fade before examination; ask for photographs and examine during a temperature spike without relying on colour description alone across skin tones.
Marked ferritin supports intense inflammation but is not specific; sepsis, liver injury, malignancy and macrophage activation also raise it.
RF and ANA are usually absent but negative serology does not prove Still disease.
Obtain repeated cultures, infection imaging and malignancy-directed assessment before major immunosuppression, guided by the exposure and organ phenotype.
Falling platelets, fibrinogen or ESR despite ongoing fever, rising triglycerides, liver injury, coagulopathy and neurological change suggests macrophage activation syndrome.
Once Still disease is established, introduce IL-1 or IL-6 inhibition as early as possible through specialist care; use systemic glucocorticoids briefly as a bridge or for severe organ disease rather than allowing prolonged steroid dependence.
Track systemic and articular phenotypes separately because some patients evolve from febrile disease into chronic destructive arthritis.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Autoinflammatory susceptibility

Innate immune dysregulation and polygenic susceptibility promote uncontrolled cytokine release without a single diagnostic autoantibody or inherited Mendelian cause.

Possible infectious triggers

Viral or other infections may precede onset in some patients, but no organism consistently explains disease and infection must remain a differential.

No single causative exposure

Drug, viral and environmental events have been reported around onset, but associations are inconsistent and no one transmissible, occupational or medication trigger explains the disease.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Innate immune cytokine surge
Activated macrophages and neutrophils release pyrogenic and inflammatory cytokines, producing quotidian fever, neutrophilia, rash and acute-phase responses.
2
Synovial and organ inflammation
Persistent cytokine signalling affects joints, liver, lymphoid tissue, serosa and lung, with variable systemic or arthritis-dominant disease.
3
Macrophage activation syndrome
Uncontrolled T-cell and macrophage activation causes haemophagocytic inflammation, cytopenia, coagulopathy, hepatic injury and potentially fatal multiorgan failure.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Quotidian febrile phenotype

High fever spikes with evanescent rash, sore throat, inflammatory arthritis and neutrophilic inflammation form a characteristic but not pathognomonic pattern.

Systemic organ disease

Lymphadenopathy, hepatosplenomegaly, hepatitis, serositis, myocarditis or lung inflammation indicates systemic burden beyond the joints.

Chronic articular phenotype

Persistent polyarthritis, wrist involvement and erosive change may dominate after fever settles and requires disease-modifying assessment.

Macrophage activation syndromeRed flag

Persistent fever with falling cell counts, fibrinogen, coagulopathy, hepatic or neurological deterioration and rising ferritin is an immediate inflammatory emergency.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serial FBC, ferritin, CRP, ESR, liver, triglycerides, fibrinogen and coagulationFirst step
Why
Characterise systemic inflammation and detect evolving macrophage activation syndrome.
Interpretation and limitations
Trends and direction matter: falling platelets or fibrinogen during ongoing fever may be more concerning than the absolute ferritin alone.
02
Blood cultures and phenotype-directed infection testing
Why
Exclude bacterial, viral, tuberculosis and opportunistic infection before and during immunosuppression.
Interpretation and limitations
Repeat cultures and image likely sources when fever persists; immunosuppression can blunt local signs and biomarkers.
03
CT, echocardiography and organ-specific imaging
Why
Assess lymph nodes, malignancy, serositis, myocarditis, lung disease, abscess and organomegaly.
Interpretation and limitations
Findings are not disease-specific; use imaging to select biopsy and identify complications or alternative diagnoses.
04
RF, ANA and other targeted autoimmune tests
Why
Assess alternative connective-tissue and inflammatory diseases within the clinical phenotype.
Interpretation and limitations
Negative RF and ANA are common in Still disease but not diagnostic, while positive low-specificity results may be incidental.
05
Bone marrow, lymph-node or other tissue sampling
Why
Investigate malignancy, infection or haemophagocytic inflammation when blood and imaging raise concern.
Interpretation and limitations
Haemophagocytosis may be absent early or occur in other severe illness; tissue results must be integrated with the complete syndrome.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Sepsis and occult infection

Endocarditis, abscess, viral infection and tuberculosis can mimic fever, rash and ferritin elevation and must be actively cultured and imaged.

Haematological malignancy

Lymphoma and leukaemia can cause fever, lymphadenopathy, cytopenia and organomegaly and may require marrow or tissue diagnosis.

Other systemic inflammatory disease

Vasculitis, lupus, drug reactions and autoinflammatory syndromes may produce overlapping fever, rash and clinically important organ inflammation.

Macrophage activation from another cause

HLH can accompany infection, malignancy or autoimmune disease, so identifying the inflammatory emergency does not establish Still disease as its trigger.

Additional chapter-specific clues

Infection or malignancy mimicRed flag

Positive cultures, focal imaging, clonal blood or tissue findings or discordant response redirects diagnosis and prevents hazardous escalation of immunosuppression.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Febrile systemic presentationExclude infection and malignancy in parallelFirst stepSpiking fever, rash, inflammatory joints and high inflammatory markers suggest Still disease without current shock.

1Obtain repeated cultures, infection and travel testing, full blood and liver assessment and imaging guided by nodes, organs and constitutional features.
2Seek rheumatology and haematology input early and arrange tissue sampling when malignancy or unusual infection remains plausible.
3Begin specialist anti-inflammatory treatment only with an explicit parallel plan for pending cultures, organ monitoring and reassessment of the diagnosis.

02Macrophage activation signalTreat the trajectory as an emergencyFever persists while platelets, fibrinogen, liver, coagulation, neurological or circulatory function deteriorates.

1Admit to monitored care, repeat FBC, ferritin, triglycerides, fibrinogen, coagulation and organ tests and sample infection urgently.
2Coordinate immediate rheumatology, haematology and critical-care treatment rather than waiting for every classification item. High-dose glucocorticoid is mandatory in MAS; consider early anakinra, ciclosporin and/or interferon-gamma inhibition in expert care while treating triggers.
3Trend laboratory and organ response closely and revise treatment for infection, malignancy or refractory cytokine activation as evidence returns.

03Confirmed active diseaseStart cytokine control and limit steroidsStill disease is established and systemic or articular inflammation requires disease-modifying treatment.

1Define systemic and articular activity, confirm that infection and malignancy evaluation remains adequate, and assess organ severity and contraindications.
2Introduce specialist IL-1 or IL-6 inhibition as early as possible. Use a short glucocorticoid bridge or severe-organ regimen, and consider methotrexate when chronic arthritis remains the dominant problem.
3Set explicit inactive-disease and taper targets, with vaccination, infection, bone, metabolic, reproductive and agent-specific laboratory monitoring.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Short, specialist bridge for significant systemic or articular inflammation, or initial control of severe organ disease, while early steroid-sparing cytokine therapy is arranged.

Prednisolone

A common specialist initial range is 0.5–1 mg/kg orally once daily for significant systemic disease, followed by a response-led taper and steroid-sparing plan.

Continue parallel infection assessment and monitor glucose, blood pressure, mood, eyes and bone. Use the shortest effective course, prevent opportunistic infection when the regimen warrants it and never stop established prolonged therapy abruptly.

IL-1 receptor antagonist introduced early for systemic or articular Still disease through specialist pathways, reducing glucocorticoid exposure rather than being reserved only for refractory illness.

Anakinra

At body weight 50 kg or more, use 100 mg subcutaneously once daily; below 50 kg, start 1–2 mg/kg/day. In severe renal impairment with creatinine clearance below 30 mL/min, consider dosing every other day.

Do not start during active serious infection and do not give live vaccines concurrently. Check neutrophils before treatment, monthly for six months and quarterly thereafter; monitor liver tests and injection reactions. Product information does not recommend routine use in pregnancy, so use specialist reproductive planning and document later-pregnancy exposure for the infant-vaccine team.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Macrophage activation syndrome

Rapid haemophagocytic inflammation causes cytopenia, liver failure, bleeding, neurological dysfunction, shock and death without immediate specialist treatment.

Chronic destructive arthritis

Persistent synovitis, particularly involving wrists, can cause progressive erosions, ankylosis, deformity and substantial long-term functional disability.

Cardiopulmonary and hepatic disease

Pericarditis, myocarditis, pleuritis, pulmonary inflammation and hepatitis can become organ-threatening and require urgent critical multidisciplinary care.

Immunosuppression toxicity

Corticosteroids and cytokine inhibitors increase infection, metabolic, bone, hepatic and haematological risks requiring prevention and structured monitoring.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During systemic activity trend temperature, FBC, ferritin, CRP, ESR, liver, triglycerides, fibrinogen and coagulation.
Monitor heart, lung, neurological, renal and circulatory function according to the organ phenotype.
Review infection continuously during glucocorticoid and cytokine-inhibitor therapy, including pending cultures.
Track swollen joints, function and imaging damage when a chronic articular pattern emerges.
Record cumulative steroid exposure and provide bone, glucose, blood-pressure, eye and vaccination protection.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Ferritin is a severity clue

Large elevations support intense inflammation but occur in infection, liver failure, malignancy and MAS, so trajectory and context matter.

Falling ESR may be ominous

ESR can fall as fibrinogen is consumed during MAS even while fever and organ failure worsen, creating dangerous false reassurance.

Rash can be fleeting

It may appear during fever and vanish before rounds, making patient photographs and examination during a spike clinically useful.

Patterns evolve

Systemic fever may settle while chronic arthritis persists, requiring a different outcome measure and steroid-sparing plan.

Exclusion remains active

New infection or malignancy can emerge during immunosuppression, so an established diagnosis does not close future fever assessment.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing Still disease from ferritin elevation alone.
02
Starting major immunosuppression without adequate infection and malignancy assessment.
03
Missing MAS because ESR falls or platelets remain within the reference range while rapidly declining.
04
Treating every recurrent fever as a flare in an immunosuppressed patient.
05
Continuing high-dose glucocorticoids without a steroid-sparing strategy.