📋 Key Information Summary
- Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder characterised by quotidian spiking fevers ≥39°C, an evanescent salmon-pink rash, arthritis, and markedly elevated serum ferritin.
- Diagnosis is clinical and requires exclusion of infection, malignancy (especially lymphoma), and other autoimmune rheumatic diseases; there is no single pathognomonic test.
- Yamaguchi criteria (≥5 features including ≥2 major) remain the standard diagnostic framework; major criteria: fever ≥39°C for ≥1 week, typical rash, arthralgia ≥2 weeks, leukocytosis with neutrophilia.
- Serum ferritin >3000 µg/L with glycosylated ferritin fraction <20% is highly specific for AOSD and should be requested as a first-line investigation.
- AOSD pathogenesis centres on an autoinflammatory cytokine storm driven by IL-1β, IL-18, and IL-6; this rationalises targeted biologic therapy.
- First-line therapy is NSAIDs for mild disease; systemic corticosteroids (prednisolone 0.5–1 mg/kg/day) remain the mainstay for moderate–severe presentations.
- Methotrexate is the preferred steroid-sparing agent; IL-1 inhibitors (anakinra, canakinumab) and IL-6 blockade (tocilizumab) are indicated for refractory or steroid-dependent disease.
- Macrophage activation syndrome (MAS) / secondary HLH is a life-threatening complication presenting with rapid cytopenias, hyperferritinaemia >10 000 µg/L, hepatitis, and coagulopathy; requires urgent high-dose methylprednisolone plus ciclosporin.
- Two clinical patterns are recognised: systemic (fever, serositis, rash, lymphadenopathy) and chronic articular (persistent polyarthritis resembling RA, but seronegative).
- Approximately 70% of patients achieve monocyclic or polycyclic remission; 20–30% develop chronic articular disease with risk of joint destruction requiring DMARD or biologic therapy.
- All serological markers (RF, ANA, anti-CCP) are characteristically negative; a positive RF or ANA should prompt reconsideration of the diagnosis.
- Aboriginal and Torres Strait Islander patients may present with delayed diagnosis due to barriers in specialist access; early referral to rheumatology and culturally safe care pathways are essential.
Introduction & Australian Epidemiology
Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder of unknown aetiology, considered the adult equivalent of systemic juvenile idiopathic arthritis (sJIA). The condition is characterised by quotidian (daily) spiking fevers, an evanescent salmon-pink macular rash, polyarthritis, and a pronounced acute-phase response dominated by extreme hyperferritinaemia. AOSD falls within the spectrum of autoinflammatory diseases driven by dysregulated innate immunity, particularly excessive interleukin-1β (IL-1β), IL-18, and IL-6 signalling.
AOSD is estimated to affect 0.1–0.4 per 100 000 population worldwide. Australian incidence data are limited, but tertiary rheumatology centres in Sydney, Melbourne, and Brisbane report managing 2–5 new cases annually per centre. The disease shows a bimodal age distribution with peaks at 15–25 years and 36–46 years, and no significant sex predilection in most series. Diagnosis is typically delayed by 3–6 months because the presentation mimics infection, lymphoma, and other systemic autoimmune conditions.
Diagnostic challenge: AOSD is a diagnosis of exclusion. Fever of unknown origin with ferritin >1000 µg/L should prompt AOSD consideration only after infection, haematological malignancy, and other rheumatic diseases (SLE, vasculitis) have been systematically excluded.
In Australia, clinicians should be aware of the high background prevalence of infections (Q fever, rickettsial disease, Ross River virus in endemic areas) that may present with fever, rash, and arthralgia — features overlapping with AOSD. A thorough infectious disease workup is mandatory before committing to an AOSD diagnosis.
Pathogenesis & Diagnostic Criteria
Pathogenesis
AOSD is classified among the monogenic and polygenic autoinflammatory diseases. The hallmark is dysregulated innate immune activation producing a cytokine storm without evidence of adaptive autoimmune T- or B-cell–mediated pathology (hence seronegative status). Key pathogenic mediators include:
- IL-1β: The dominant cytokine. Activated macrophages and neutrophils release IL-1β via the NLRP3 inflammasome, driving fever, rash, synovitis, and acute-phase reactant elevation. IL-1β blockade is the most effective targeted therapy.
- IL-18: Markedly elevated in AOSD (often >10 × upper limit of normal); correlates with disease activity and MAS risk. IL-18–binding protein levels may be relatively insufficient.
- IL-6: Produced downstream of IL-1β stimulation; responsible for CRP, ferritin, and hepcidin upregulation. Contributes to the anaemia of chronic disease.
- IL-17 and Th17 axis: Emerging evidence of Th17 skewing, particularly in the chronic articular phenotype.
- Neutrophil activation: Neutrophilia and neutrophilic infiltration of synovium, liver, serosal surfaces, and reticuloendothelial system explain the organomegaly and serositis.
Ferritin biology in AOSD: Hyperferritinaemia in AOSD is not related to iron overload. IL-6 drives hepatic ferritin synthesis while simultaneously suppressing its glycosylation. The resulting low glycosylated ferritin fraction (<20%) is a near-pathognomonic laboratory finding when combined with extreme hyperferritinaemia.
Diagnostic Criteria
No single test confirms AOSD. The Yamaguchi criteria (1992) remain the most widely validated classification set. They require ≥5 features including ≥2 major criteria, with exclusion of infection, malignancy, and other rheumatic diseases.
| Yamaguchi Criterion | Major | Minor |
|---|---|---|
| Fever ≥39°C for ≥1 week | ✔ | |
| Typical rash (evanescent, salmon-pink, coinciding with fever) | ✔ | |
| Arthralgia or arthritis ≥2 weeks | ✔ | |
| Leukocytosis (≥10 × 10⁹/L) with neutrophilia (≥80%) | ✔ | |
| Sore throat | ✔ | |
| Lymphadenopathy and/or splenomegaly | ✔ | |
| Liver dysfunction (elevated transaminases) | ✔ | |
| Negative RF and ANA | ✔ |
Supportive Biomarkers (Not in Yamaguchi but Clinically Essential)
- Serum ferritin >1000 µg/L: Present in >80% of patients; values >3000 µg/L are highly suggestive.
- Glycosylated ferritin <20%: Highly specific for AOSD; normal glycosylated ferritin is 20–50%. Request this test early — available at major Australian hospital laboratories (MBS item 66835 for serum ferritin; glycosylated fraction may require specialist laboratory referral).
- Elevated IL-18: Research biomarker; not yet standard in Australian pathology panels but available at reference laboratories.
- Marked elevation of ESR, CRP, LDH: Non-specific but correlate with disease activity.
Diagnostic pearl: Ferritin >3000 µg/L + glycosylated ferritin <20% + seronegative polyarthritis + quotidian fever = AOSD until proven otherwise. Even so, always exclude lymphoma (CT-PET, bone marrow biopsy if indicated).
Clinical Features & Complications
Classic Presentation
AOSD typically presents with a dramatic systemic illness. The hallmark features are:
- Quotidian (daily) spiking fever: Temperature ≥39°C, often rising to 40°C in the late afternoon/evening, then returning to normal or subnormal by morning. This double-quotidian pattern (two spikes per day) is virtually pathognomonic when present.
- Salmon-pink evanescent rash: A faint macular or maculopapular rash, 2–5 mm, non-pruritic, classically on the trunk and proximal limbs, typically appearing during febrile episodes and fading within hours. Koebner phenomenon may occur. Skin biopsy shows mild perivascular lymphocytic infiltration.
- Arthritis: Usually symmetric polyarthritis affecting wrists, knees, ankles, and small joints of the hands. May present early as arthralgia without clinical synovitis. Chronic articular disease can cause erosive joint destruction resembling rheumatoid arthritis.
- Sore throat: Severe pharyngitis, often preceding or coinciding with febrile episodes; may be the presenting complaint.
- Hepatosplenomegaly: Mild–moderate hepatomegaly and/or splenomegaly due to reticuloendothelial activation.
- Lymphadenopathy: Generalised, non-tender; occasionally marked enough to raise lymphoma concern.
- Serositis: Pleuritis, pericarditis, or both; pericardial effusion may be clinically significant.
Two Clinical Phenotypes
| Feature | Systemic Pattern | Chronic Articular Pattern |
|---|---|---|
| Proportion | ~60–70% | ~30–40% |
| Fever | Dominant, quotidian | Less prominent or absent |
| Rash | Prominant, evanescent | Mild or absent |
| Arthritis | Mild, self-limiting | Deforming, erosive |
| Course | Monocyclic (~60%) or polycyclic (~15%) | Chronic, persistent (~25%) |
| Treatment | NSAIDs → steroids ± biologics | DMARDs + biologics |
Complications
Macrophage Activation Syndrome (MAS) / Secondary HLH: The most feared complication of AOSD, occurring in 10–15% of patients. MAS represents a cytokine-driven hyperinflammatory state with uncontrolled macrophage and T-cell activation. Presents with rapid clinical deterioration: persistent high fever unresponsive to steroids, cytopenias (falling platelets, WBC), coagulopathy (falling fibrinogen, rising D-dimer), hepatitis (ALT >10 × ULN), and hyperferritinaemia >10 000 µg/L. Requires immediate high-dose IV methylprednisolone (500–1000 mg daily × 3 days) plus ciclosporin 2–5 mg/kg/day. Transfer to a tertiary centre with haematology expertise. Mortality 10–20% even with treatment.
HLH-2004 Diagnostic Criteria for MAS (Modified for AOSD)
- Fever
- Splenomegaly
- Cytopenias (2 of 3: Hb <90 g/L, platelets <100 × 10⁹/L, neutrophils <1.0 × 10⁹/L)
- Hypertriglyceridaemia (>2.0 mmol/L) and/or hypofibrinogenaemia (<1.5 g/L)
- Haemophagocytosis on bone marrow, spleen, or lymph node biopsy
- Hyperferritinaemia >10 000 µg/L (AOSD-adapted threshold)
- Elevated soluble IL-2 receptor (sCD25) >2400 U/mL
- Low or absent NK-cell activity
Other Complications
- Diffuse alveolar haemorrhage: Rare but life-threatening; presents with haemoptysis, hypoxia, and diffuse ground-glass opacities on CT chest.
- Myocarditis / pericarditis: May cause tamponade or heart failure.
- Reactive amyloidosis (AA): Chronic inflammation may lead to AA amyloidosis with nephrotic syndrome; monitors with urinary protein-to-creatinine ratio.
- Drug-related complications: Steroid osteoporosis, avascular necrosis, diabetes; methotrexate hepatotoxicity; biologic infection risk.
- Thrombotic microangiopathy: Reported in severe AOSD; may mimic TTP/HUS.
Investigations
Investigation in AOSD serves two purposes: supporting the diagnosis and excluding mimics. A systematic approach is essential.
Baseline Investigations
Essential
FBC with differential
Leukocytosis ≥10 × 10⁹/L with neutrophilia ≥80%; reactive thrombocytosis in active disease; cytopenias suggest MAS.
Essential
ESR & CRP
Markedly elevated in active disease; monitor for treatment response.
Essential
Serum ferritin (MBS 66835)
Usually >1000 µg/L; >3000 highly suggestive. Repeat if MAS suspected (>10 000 triggers urgent workup).
Essential
Glycosylated ferritin fraction
<20% is highly specific. Available at major hospital reference labs. Request in conjunction with total ferritin.
Essential
LFTs (ALT, AST, ALP, bilirubin)
Hepatitis is common in AOSD and prominent in MAS.
Essential
Coagulation (INR, APTT, fibrinogen, D-dimer)
Hypofibrinogenaemia and elevated D-dimer indicate MAS.
Essential
RF, ANA, anti-CCP
Characteristically negative. If positive, reconsider diagnosis.
Available
Blood cultures × 2 sets
To exclude bacteraemia, endocarditis, Q fever.
Available
Serum LDH, triglycerides
Elevated LDH in active AOSD; triglycerides >2.0 mmol/L in MAS.
Referral
Soluble IL-2 receptor (sCD25) / IL-18 levels
Reference lab test; sCD25 >2400 U/mL supports MAS; IL-18 correlates with disease activity.
Exclusion Investigations
Essential
CT chest/abdomen/pelvis with contrast
Exclude lymphoma, solid organ malignancy, and hepatosplenomegaly assessment.
Referral
PET-CT
Useful if lymphoma is a differential; AOSD shows diffuse marrow and splenic uptake.
Referral
Bone marrow biopsy
If MAS suspected or to exclude haematological malignancy; haemophagocytosis may be seen.
Available
Serology: Q fever, HIV, hepatitis B/C, EBV, CMV
Essential in the Australian context to exclude tropical and endemic infections.
Available
Urinalysis and urine protein-to-creatinine ratio
Screen for amyloid nephropathy in chronic disease.
Imaging
- Synovial ultrasound/MRI: Detects early synovitis and erosions in chronic articular disease.
- Echocardiography: If pericarditis or myocarditis suspected; pericardial effusion is common.
- High-resolution CT chest: If pulmonary symptoms; ground-glass opacities may indicate DAH or organising pneumonia.
Risk Stratification & Disease Course
AOSD follows three recognised clinical courses, each with distinct prognostic implications:
Monocyclic
Self-Limiting Systemic
Single episode lasting weeks to months, followed by complete remission without relapse. Most common pattern (~60%). Requires initial high-dose steroid taper over 3–6 months.
Setting: Rheumatology outpatient, GP shared care
Polycyclic
Relapsing–Remitting
Recurrent flares separated by remission periods (months to years). Flares often triggered by intercurrent infection, stress, or steroid tapering. ~15% of patients.
Setting: Rheumatology outpatient; consider steroid-sparing agent early
Chronic Articular
Persistent Disease
Persistent polyarthritis resembling RA, often erosive. Systemic features may attenuate over time. ~25% of patients. Requires DMARD ± biologic therapy. Worse functional prognosis.
Setting: Rheumatology specialist; may need DMARDs/biologics; monitor joint destruction
Predictors of Poor Outcome
- Chronic articular disease pattern
- Steroid dependence / refractory disease
- Development of MAS
- Hip or large-joint arthritis at presentation
- Elevated IL-18 and ferritin at baseline (paradoxically associated with worse outcomes)
- Delay to diagnosis >6 months
Management
Treatment of AOSD follows a stepwise approach from NSAIDs to corticosteroids, conventional DMARDs, and targeted biologics. The choice depends on disease severity, pattern (systemic vs chronic articular), and response to therapy.
Stepwise Treatment Algorithm
Step 1
NSAIDs (Mild Disease)
First-line for mild systemic symptoms. Indomethacin 50–75 mg TDS or naproxen 500 mg BD PO. Response in ~20% of patients. Adequate trial 2–4 weeks before escalating.
Step 2
Systemic Corticosteroids (Mainstay)
Prednisolone 0.5–1 mg/kg/day (max 60 mg) PO for moderate–severe systemic disease. IV methylprednisolone 500–1000 mg daily × 3 days for severe/refractory. Taper over 3–6 months once CRP normalised.
Step 3
Steroid-Sparing DMARDs
Methotrexate (MTX) 7.5–25 mg/week PO or SC + folic acid 5 mg weekly. First choice if steroid-dependent or chronic articular disease. Cyclosporin A 2–5 mg/kg/day as alternative.
Step 4
Targeted Biologics (Refractory)
IL-1 inhibitors: anakinra (1st choice), canakinumab. IL-6 inhibitor: tocilizumab. TNF inhibitors for chronic articular pattern. Used when conventional therapy fails.
Drug Detail
Indomethacin
Indocid® · NSAID · First-line for mild AOSD
Adult dose
50–75 mg PO TDS with food
Paediatric dose
1–2 mg/kg/day in 2–3 divided doses
Route
Oral
Duration
2–4 week trial; continue if responsive
Renal adjustment
Avoid if eGFR <30 mL/min
PBS status
✔ PBS General Benefit
Prednisolone
Solone® · Panafcortelone® · Corticosteroid · Mainstay therapy
Adult dose
0.5–1 mg/kg/day PO (max 60 mg); taper over 3–6 months
Paediatric dose
1–2 mg/kg/day PO; taper as per sJIA protocols
Route
Oral (PO); IV methylprednisolone 500–1000 mg/day × 3 days for severe
Duration
3–6 months minimum; long-term if chronic articular
Renal adjustment
No adjustment; monitor fluid retention
PBS status
✔ PBS General Benefit
Methotrexate
Methoblastin® · Injectable · DMARD · Steroid-sparing agent
Adult dose
7.5–25 mg/week PO or SC; escalate by 2.5 mg every 2–4 weeks
Paediatric dose
10–15 mg/m²/week PO or SC
Route
Oral or subcutaneous injection
Duration
Long-term if steroid-dependent or chronic articular
Key monitoring
FBC, LFTs every 2–4 weeks initially; FBC 6–8 weekly once stable
Renal adjustment
Reduce dose if eGFR <30 mL/min or avoid
PBS status
✔ PBS General Benefit
Anakinra
Kineret® · IL-1 receptor antagonist · 1st choice biologic
Adult dose
100 mg SC daily; some centres use 100 mg BD for severe systemic disease
Paediatric dose
1–2 mg/kg/day SC (max 100 mg)
Route
Subcutaneous injection
Duration
Ongoing if responsive; rapid onset (within 24–48 hours)
Key monitoring
Injection site reactions (common); infection risk; neutrophil count
Renal adjustment
No specific adjustment; use with caution in severe renal impairment
PBS status
✘ Not PBS for AOSD (off-label use; may require Authority/special access)
Canakinumab
Ilaris® · Anti-IL-1β monoclonal antibody
Adult dose
150 mg SC every 4–8 weeks; dose titration based on response
Route
Subcutaneous injection
Duration
Ongoing; longer half-life than anakinra allows less frequent dosing
Key monitoring
Infection risk; neutropenia; hepatic function
PBS status
✘ Not PBS for AOSD (PBS-listed for sJIA; may require special access for AOSD)
Tocilizumab
Actemra® · Anti-IL-6 receptor antibody
Adult dose
4 mg/kg IV every 2–4 weeks; or 162 mg SC weekly
Route
IV infusion or subcutaneous injection
Duration
Ongoing; particularly useful in chronic articular phenotype
Key monitoring
CRP unreliable on therapy (masks infection); lipids; LFTs; neutrophil count
PBS status
⚠ PBS Restricted Benefit (for specific indications; may require authority for AOSD)
Ciclosporin
Neoral® · Sandimmun® · Calcineurin inhibitor
Adult dose
2–5 mg/kg/day PO in 2 divided doses
Route
Oral (or IV in MAS)
Primary indication
MAS rescue therapy (with high-dose methylprednisolone); alternative steroid-sparing agent
Key monitoring
Renal function, BP, drug trough levels, Mg²⁺
PBS status
✔ PBS General Benefit
Management of MAS / HLH
MAS Emergency Protocol:
- Immediate: IV methylprednisolone 500–1000 mg daily × 3 days
- Concurrent: Ciclosporin 2–5 mg/kg/day (oral or IV) — initiate within 24 hours of MAS diagnosis
- If refractory to 48 hours of high-dose steroids + ciclosporin: Consider anakinra 1–2 mg/kg/day SC/IV; etoposide (per HLH-94 protocol) only under haematology guidance
- Supportive: ICU admission for haemodynamic monitoring; blood product support (FFP, cryoprecipitate for DIC); avoid unnecessary NSAIDs (renal/bleeding risk)
- Treat trigger: If concurrent infection identified, treat aggressively; stop any causative drug
Treatment of Chronic Articular Disease
The chronic articular phenotype requires a rheumatoid arthritis–like approach:
- Methotrexate: First-line DMARD; escalate to 25 mg/week if needed.
- Leflunomide: Alternative if MTX contraindicated; 20 mg/day PO.
- Biologics: IL-1 inhibitors (anakinra) for systemic flares; tocilizumab or TNF inhibitors (adalimumab, etanercept) for articular predominance.
- Intra-articular corticosteroids: For persistent mono/oligoarthritis.
Monitoring
Disease Activity Monitoring
- CRP and ESR: Every 2–4 weeks during active treatment; every 1–3 months in remission.
- Serum ferritin and glycosylated ferritin: Baseline and with each flare; falling ferritin and rising glycosylated fraction indicates response.
- FBC: Monitor for cytopenias (MAS) and drug toxicity (MTX, ciclosporin).
- LFTs:
Special Populations
Pregnancy
Prednisolone
Safe in pregnancy; lowest effective dose. Continue if active disease.
Methotrexate
Contraindicated — teratogenic (Category X). Stop ≥3 months before conception.
Anakinra
Category B3; limited data. Consider if uncontrolled disease — shared decision with maternal–fetal medicine.
Tocilizumab
Contraindicated in pregnancy (animal data: increased resorption). Stop ≥3 months before planned conception.
Ciclosporin
Can be continued in pregnancy if essential; monitor renal function and BP.
NSAIDs
Avoid in third trimester (premature ductus arteriosus closure). Short-term use in first/second trimester acceptable.
Paediatrics (<16 years)
Diagnosis
Consider systemic JIA (sJIA) if age <16; identical pathophysiology. Use sJIA classification criteria.
Anakinra
PBS-listed for sJIA; 1st-line biologic. 1–2 mg/kg/day SC.
Canakinumab
PBS-listed for sJIA; 4 mg/kg SC every 4 weeks (max 300 mg).
Tocilizumab
PBS-listed for sJIA; weight-based IV dosing every 2 weeks.
MAS risk
Higher MAS risk in paediatric sJIA; monitor closely at each visit.
Elderly (≥65 years)
NSAIDs
Use with caution; higher GI bleeding and renal risk. Co-prescribe PPI. Avoid in CKD.
Corticosteroids
Increased risk of osteoporosis, diabetes, falls. Start bone protection (alendronate) early; monitor BGL.
Methotrexate
Lower starting dose (5–7.5 mg/week); enhanced hepatic/renal monitoring.
Biologics
Higher infection risk; screen for latent TB and hepatitis B before commencing.
Renal Impairment
NSAIDs
Avoid if eGFR <30 mL/min; use with caution if eGFR 30–60.
Methotrexate
Dose reduce or avoid if eGFR <30; monitor closely if eGFR 30–60.
Ciclosporin
Nephrotoxic; avoid if eGFR <50; requires therapeutic drug monitoring.
Corticosteroids
Safe but monitor fluid balance; use lowest effective dose.
Hepatic Impairment
Methotrexate
Contraindicated in significant liver disease; AOSD itself causes hepatitis — monitor LFTs closely.
Corticosteroids
Safe; may improve AOSD-related hepatitis.
Anakinra
No specific hepatic adjustment; preferred biologic in hepatic disease.
Immunocompromised
Biologics
Screen for latent TB (IGRA), hepatitis B/C, HIV before commencing. Avoid live vaccines on biologics. Ensure influenza and pneumococcal vaccination is up to date.
MAS risk
Immunosuppressive therapy increases infection risk, which may trigger MAS. Vigilant infection surveillance.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
📚 References
- 1. Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P. Adult-onset Still's disease. Autoimmun Rev. 2014;13(7):708-722.
- 2. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19(3):424-430.
- 3. 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.
- 4. Mitrovic S, Fautrel B. New insights into the pathogenesis and the therapeutic landscape of adult-onset Still's disease. Joint Bone Spine. 2018;85(5):547-553.
- 5. Hinojosa-Azaola A, García-García C, Jiménez-Balderas FJ. Macrophage activation syndrome in adult-onset Still's disease. Med Clin (Barc). 2018;151(8):323-329.
- 6. Colafrancesco S, Priori R, Valesini G, et al. Response to interleukin-1 inhibitors in adult-onset Still's disease: a nationwide study of 103 Italian patients. J Rheumatol. 2019;46(12):1647-1652.
- 7. Nirmala N, Brachat A, Feist E, et al. Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. Pediatr Rheumatol. 2015;13:50.
- 8. Helliwell T, Muller S, Hider SL, et al. Challenges of diagnosing and managing adult-onset Still's disease in primary care. Rheumatol Adv Pract. 2020;4(2):rkaa043.
- 9. Australian Institute of Health and Welfare (AIHW). Aboriginal and Torres Strait Islander Health Performance Framework 2023. Canberra: AIHW; 2023.
- 10. Ranzolin A, Bredemeier M, Wobeto C, et al. Adult-onset Still's disease in South America: a Brazilian multicentre study. Clin Rheumatol. 2020;39(7):2129-2136.
- 11. Efthimiou P, Kontzias A, Ward CM, Ogden NS. Adult-onset Still's disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy? Nat Clin Pract Rheumatol. 2007;3(6):328-335.
- 12. Canna SW, de Jesus AA, Gouni S, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140-1146.
- 13. National Health and Medical Research Council (NHMRC). Australian Guidelines for the Clinical Care of People with CKD. Canberra: NHMRC; 2024 (relevant for renal dosing guidance).
- 14. Ruscitti P, Cipriani P, Masedu F, et al. Adult-onset Still's disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers. BMC Med. 2016;14:194.
- 15. Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.