Adult-onset Still disease (AOSD)
Description
- A systemic AUTOINFLAMMATORY disease - innate immunity, not autoantibodies
- *The four cardinal features*
- FEVER - quotidian (once or twice daily) spikes >39 degrees C, returning to normal between
- ARTHRITIS / ARTHRALGIA
- EVANESCENT SALMON-PINK MACULAR RASH
- LEUCOCYTOSIS WITH NEUTROPHILIA
- *A diagnosis of exclusion* - infection, malignancy and other connective tissue disease must be excluded first
- The adult counterpart of systemic juvenile idiopathic arthritis - now regarded as one disease across the age spectrum
Epidemiology
- Rare: incidence ~0.1-0.4 per 100,000/yr
- F = M (or slight female excess)
- Bimodal age peaks: 15-25 and 36-46
- Accounts for ~5-10% of cases of pyrexia of unknown origin
- *Macrophage activation syndrome (MAS/HLH) complicates ~10-15%* - the main cause of death
Aetiopathogenesis
- Innate immune activation without a demonstrable autoantibody or antigen-specific T-cell response
- *IL-1beta and IL-18 are the central cytokines (inflammasome-driven), with IL-6, IL-17, TNF-alpha and interferon-gamma*
- IL-18 is characteristically and extremely raised - a useful biomarker where available, and the link to macrophage activation syndrome
- *That IL-1 is central is why anakinra and canakinumab work so well - often within days*
- Neutrophil and macrophage activation -> ferritin release and hepatic synthesis -> HYPERFERRITINAEMIA
- Glycosylated ferritin falls (normally 50-80% of ferritin is glycosylated; <20% in AOSD**) - because glycosylation sites are saturated by massive secretion
- Possible infectious triggers (Yersinia, Chlamydia, rubella, EBV, CMV, parvovirus) and HLA associations (HLA-B17, B18, B35, DR2)
Diagnosis
Clinical features
- Fever - *quotidian spiking, usually late afternoon/evening, with a return to baseline*; present in >95%
- Rash - *EVANESCENT, salmon-pink, macular/maculopapular, on the trunk and proximal limbs, appearing WITH the fever spike and gone by morning*
- Koebner phenomenon and dermographism; often missed because the patient is examined in the morning
- Arthritis - initially oligoarticular and migratory, later symmetrical polyarthritis; wrist, knee, ankle
- *Carpal ankylosis (non-erosive fusion of the carpometacarpal and intercarpal joints) is characteristic*
- Sore throat - culture-negative, non-exudative, often at the very onset and a useful historical clue
- Lymphadenopathy, hepatosplenomegaly, serositis (pleuritis, pericarditis), myalgia
- Weight loss, abdominal pain
Laboratory
- *Markedly raised FERRITIN - often >1,000 microg/L, and >5x ULN is characteristic*
- Glycosylated ferritin <20% - more specific
- Neutrophil leucocytosis, often >15 x 10^9/L with >80% neutrophils
- Very high ESR and CRP; anaemia of inflammation, thrombocytosis
- Abnormal LFTs (transaminitis) in ~75%
- *RF and ANA NEGATIVE* - a positive result should prompt reconsideration
- Raised IL-18 where available
Yamaguchi criteria - >=5 criteria with >=2 major, and all exclusions met
| Major | Minor |
|---|---|
| Fever >=39 degrees C for >=1 week | Sore throat |
| Arthralgia >=2 weeks | Lymphadenopathy and/or splenomegaly |
| Typical rash | Abnormal liver function tests |
| Leucocytosis >=10 x 10^9/L with >=80% neutrophils | Negative RF and negative ANA |
- Exclusions: infection (especially sepsis and EBV), malignancy (especially LYMPHOMA), and other rheumatic disease (especially vasculitis)
- The Fautrel criteria add ferritin >5x normal and glycosylated ferritin <=20% and do not require exclusions
Work-up - because it is a diagnosis of exclusion
- Blood cultures x3, urine culture, viral serology (EBV, CMV, parvovirus, HIV, hepatitis), echocardiogram for endocarditis
- CT chest/abdomen/pelvis; consider PET-CT - lymphoma is the critical mimic
- Lymph node biopsy if lymphadenopathy is prominent (AOSD nodes show reactive paracortical hyperplasia, which can be misread as lymphoma - and vice versa)
- Bone marrow biopsy - exclude haematological malignancy and look for haemophagocytosis
- ANA, ENA, ANCA, RF, anti-CCP, complement
Recognise macrophage activation syndrome (HLH)
- *Suspect when a patient with AOSD deteriorates and the ESR FALLS or cytopenias appear*
- Ferritin often >10,000, falling ESR (fibrinogen consumption), cytopenias, hypertriglyceridaemia, hypofibrinogenaemia, transaminitis, raised soluble CD25, haemophagocytosis on marrow
- Persisting fever with a falling platelet count is the classic warning
Management
By disease severity and phenotype
1. Mild disease (fever, rash, arthralgia, no organ involvement)
- NSAIDs at full dose - control in only ~20-25% alone
- Short course of prednisolone if NSAIDs fail
2. Moderate-severe systemic disease
- Prednisolone 0.5-1 mg/kg/day, or IV methylprednisolone pulses if organ-threatening
- Responds in ~60-80%, but steroid dependence is the rule
- *Start a steroid-sparing agent early*
- Methotrexate - best for the chronic articular phenotype
- Ciclosporin, azathioprine, leflunomide as alternatives
3. Biologics - by phenotype (the modern approach)
| Phenotype | Preferred biologic |
|---|---|
| *SYSTEMIC* (fever, rash, serositis, high ferritin) | *IL-1 blockade: ANAKINRA (often a dramatic response within 24-72 h), canakinumab* |
| *CHRONIC ARTICULAR* (persistent polyarthritis) | *IL-6 blockade: TOCILIZUMAB*; methotrexate |
| Refractory to both | TNF inhibitors (less effective), abatacept, JAK inhibitors (emerging) |
- *Anakinra is both therapeutic and diagnostic* - a rapid, complete response strongly supports the diagnosis
- Australian access: anakinra and canakinumab require PBS authority or Special Access Scheme pathways; tocilizumab is PBS-listed for sJIA/AOSD in defined circumstances
4. Macrophage activation syndrome - a medical emergency
- High-dose corticosteroid (IV methylprednisolone) + ciclosporin, anakinra
- Etoposide-based HLH protocol if refractory
- Emapalumab (anti-interferon-gamma) in refractory disease
- Stop any potential trigger drug; exclude concurrent EBV or other infection
5. Supportive
- Bone protection, PJP prophylaxis on high-dose steroids, vaccination, infection screening before biologics (hepatitis B/C, HIV, latent TB)
Associations
- Macrophage activation syndrome / secondary HLH - the most feared complication
- Reactive haemophagocytic syndrome, disseminated intravascular coagulation
- Serositis - pericarditis, pleuritis, rarely tamponade; myocarditis
- Pulmonary: pleural effusion, acute respiratory distress syndrome, *pulmonary arterial hypertension and alveolar proteinosis (an emerging, serious association, particularly in sJIA*)
- Amyloidosis (AA) - chronic uncontrolled disease
- Fulminant hepatitis, thrombotic microangiopathy
- *Systemic JIA* - the same disease in children
- Lymphoma - the key differential, and lymphoma can also arise later; re-image any atypical relapse
- Other autoinflammatory syndromes (FMF, TRAPS, CAPS, Schnitzler) - the differential for periodic fever with rash
Natural history & complications
Three recognised patterns
| Pattern | Frequency | Course |
|---|---|---|
| Monocyclic (self-limiting) | ~20-35% | A single episode resolving within 1 year - best prognosis |
| Polycyclic (intermittent) | ~30-40% | Recurrent flares with remissions of months to years |
| Chronic articular | ~35-40% | *Persistent destructive polyarthritis - the main cause of long-term disability* |
- Overall prognosis is good; 10-year survival >90%
- Poor prognostic factors: polyarthritis at onset (especially shoulder or hip), erosive disease, need for >2 years of corticosteroid, and MAS
- *Death is from macrophage activation syndrome, infection (from immunosuppression), fulminant hepatitis, DIC and amyloidosis* - not from the fever
- Carpal ankylosis and hip destruction are the characteristic long-term joint outcomes
- Relapse can occur years later, including in pregnancy and the post-partum period
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