📋 Key Information Summary
- Autoinflammatory diseases are disorders of innate immunity with recurrent, unprovoked systemic inflammation; they lack pathogenic autoantibodies or autoreactive T-cells.
- Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease; treat with colchicine as first-line prophylaxis.
- Cryopyrin-associated periodic syndromes (CAPS) — comprising FCAS, MWS, NOMID — respond dramatically to IL-1 blockade.
- TRAPS (TNF-receptor–associated periodic syndrome) and HIDS (hyper-IgD syndrome / mevalonate kinase deficiency) should be considered in undifferentiated recurrent fever.
- Adult-onset Still disease (AOSD) presents with quotidian spiking fevers, evanescent salmon rash, and marked hyperferritinaemia.
- IL-1 inhibitors (anakinra, canakinumab, rilonacept) are the cornerstone therapy for most monogenic autoinflammatory diseases.
- Genetic testing via next-generation sequencing panels is now available through Australian public genetics services (MBS rebate applicable).
- Serum amyloid A (SAA)-driven AA amyloidosis is the most feared long-term complication of uncontrolled autoinflammation.
- Inflammasomopathies — including PAPA, DADA2, DIRA, HA20 — are NLRP3/inflammasome-mediated entities with IL-1 or TNF-α responsiveness.
- Special populations — pregnancy, paediatrics, renal impairment — require tailored dosing and monitoring of IL-1 inhibitors.
- Aboriginal and Torres Strait Islander peoples may face delayed diagnosis due to geographic and systemic barriers; ensure culturally safe referral pathways.
Introduction & Australian Epidemiology
Autoinflammatory diseases are rare disorders characterised by dysregulation of the innate immune system, leading to sterile, recurrent episodes of inflammation. Unlike autoimmune conditions, they lack high-titre autoantibodies or antigen-specific T-cell responses. Central pathogenic mechanisms involve aberrant activation of the NLRP3 inflammasome, excessive IL-1β, TNF-α, or other innate cytokine production.
In Australia, monogenic autoinflammatory diseases are estimated to affect 1–3 per 100,000 population, though FMF prevalence is higher in communities with Mediterranean or Middle Eastern ancestry. Adult-onset Still disease is more common, with an estimated incidence of 0.16 per 100,000 per year. Significant diagnostic delay (mean 5–10 years for monogenic conditions) remains a key challenge in the Australian setting.
Management centres on achieving sustained inflammatory control to prevent AA amyloidosis, leveraging IL-1 and targeted cytokine inhibition. Australian specialists should coordinate through multidisciplinary teams involving rheumatology, immunology, genetic medicine, and nephrology.
Familial Mediterranean Fever (FMF)
Overview
FMF is an autosomal-recessive disorder caused by pathogenic variants in MEFV (chromosome 16p13.3) encoding pyrin. It is the most common monogenic autoinflammatory disease worldwide, particularly prevalent in Mediterranean, Middle Eastern, and Armenian populations. In Australia, FMF is seen in individuals of Lebanese, Turkish, Armenian, Jewish, and Arab descent.
Clinical Features
- Recurrent, self-limiting febrile episodes (1–3 days), typically with serositis (peritonitis, pleuritis, pericarditis)
- Erysipelas-like erythema over the lower limbs
- Acute monoarthritis (large joints)
- In children: episodes may be shorter and more frequent; scrotal oedema is a recognised feature
- AA amyloidosis is the major long-term complication — 60–70% risk without prophylaxis
Diagnosis
Clinical diagnosis supported by Tel-Hashomer criteria; genetic confirmation with MEFV genotyping (MBS-rebated). Common Australian-pathogenic variants: M694V, V726A, M680I. Compound heterozygotes may present with milder phenotype.
Treatment
Colchicine
Colgout® · Generic · Antimitotic
Adult dose
1–2 mg/day PO (divided BID); max 2 mg/day
Paediatric dose
<5 yr 0.3–0.5 mg/day; 5–10 yr 0.5–1 mg/day; >10 yr adult dose
Renal adjustment
eGFR <30: reduce 50%; caution with concomitant statins/macrolides
PBS status
✔ PBS General Benefit
Anakinra
Kineret® · IL-1 receptor antagonist
Adult dose
100 mg SC daily for colchicine-resistant FMF
Paediatric dose
1–2 mg/kg/day SC; max 100 mg/day
PBS status
⚠ PBS Authority Required
Amyloidosis surveillance: Monitor serum amyloid A (SAA) and urine protein/creatinine ratio every 6–12 months. Target SAA <10 mg/L. Sustained elevation warrants escalation to IL-1 inhibition.
Cryopyrin-Associated Periodic Syndromes (CAPS)
Spectrum
CAPS are autosomal-dominant gain-of-function variants in NLRP3 (CIAS1), leading to constitutive inflammasome activation and IL-1β overproduction. Three severity phenotypes exist on a continuum:
Mild
FCAS (Familial Cold Autoinflammatory Syndrome)
Urticaria-like rash triggered by cold exposure; fever, arthralgia, conjunctivitis; onset <6 months of age
Setting: outpatient rheumatology
Moderate
MWS (Muckle-Wells Syndrome)
Chronic urticaria, sensorineural hearing loss, AA amyloidosis risk; not cold-dependent
Setting: specialist rheumatology/immunology
Severe
NOMID / CINCA
Neonatal-onset multisystem inflammatory disease; aseptic meningitis, uveitis, arthropathy, sensorineural deafness
Setting: tertiary paediatric centre
Treatment
- Canakinumab (Ilaris®) 150 mg SC every 8 weeks for MWS/FCAS; 2–4 mg/kg (max 300 mg) every 4–8 weeks for NOMID — ⚠ PBS Authority Required
- Anakinra (Kineret®) 1–2 mg/kg/day SC — alternative; ⚠ PBS Authority Required
- IL-1 blockade is lifelong; withdrawal leads to rapid disease flare
- NSAIDs and corticosteroids are ineffective as monotherapy
TRAPS & HIDS
| Feature | TRAPS | HIDS (MKD) |
|---|---|---|
| Gene | TNFRSF1A | MVK |
| Inheritance | Autosomal dominant | Autosomal recessive |
| Episode duration | 1–3 weeks (longer than FMF) | 3–7 days |
| Hallmark features | Migratory myalgia, centrifugal erythematous rash, periorbital oedema | Cervical lymphadenopathy, abdominal pain, elevated IgD (>100 IU/mL) |
| 1st-line Rx | Corticosteroids (acute); NSAIDs | NSAIDs, corticosteroids (limited efficacy) |
| Targeted therapy | Etanercept or IL-1 inhibitor | Anakinra (acute/rescue) or canakinumab (prophylaxis) |
| PBS access | ⚠ Authority Required | ⚠ Authority Required |
Amyloidosis risk: TRAPS carries a significant risk of AA amyloidosis (~15–25%), particularly with the R92Q low-penetrance variant. HIDS carries a lower but non-zero risk. Serial SAA monitoring is essential.
Adult-Onset Still Disease (AOSD)
Clinical Presentation
AOSD is a polygenic autoinflammatory condition with characteristic features:
- Quotidian (daily) spiking fevers ≥39°C, often with a single daily spike ("double quotidian" pattern in ~20%)
- Evanescent salmon-pink macular rash (trunk/proximal limbs, coincides with fever)
- Arthritis (wrists, knees, ankles); chronic in ~50%
- Sore throat (pharyngitis) — a classic early symptom
- Lymphadenopathy, hepatosplenomegaly, serositis
- Markedly elevated ferritin (often >1,000 µg/L; >10,000 µg/L raises macrophage activation syndrome concern)
Diagnostic Criteria (Yamaguchi, modified)
Requires ≥5 criteria (including ≥2 major), after excluding infection, malignancy, and other rheumatic diseases.
| Major Criteria | Minor Criteria |
|---|---|
| Fever ≥39°C, intermittent, ≥1 week | Sore throat |
| Arthralgia ≥2 weeks | Lymphadenopathy |
| Typical rash (salmon, evanescent) | Hepatomegaly or splenomegaly |
| Leukocytosis ≥10×10⁹/L (≥80% neutrophils) | Abnormal liver function tests |
| Negative RF and ANA |
Treatment Ladder
- 1st-line: NSAIDs (indomethacin 50 mg TDS PO) — symptom control
- 2nd-line: Corticosteroids (prednisolone 0.5–1 mg/kg/day PO, taper over weeks)
- Steroid-sparing / refractory: Methotrexate 10–25 mg/week PO/SC — ✔ PBS General Benefit
- IL-1 blockade (biologic-refractory): Anakinra 100 mg SC daily or canakinumab 150 mg SC q8w — ⚠ PBS Authority Required
- Refractory: Tocilizumab 8 mg/kg IV q4w (limited data); cyclosporin A as rescue
Macrophage activation syndrome (MAS): Ferritin >10,000 µg/L, falling fibrinogen, cytopenias, hepatopathy → haematological emergency. Treat with IV methylprednisolone pulse (1 g × 3 days) ± cyclosporin A. Transfer to tertiary centre.
Inflammasomopathies & IL-1 Inhibitors
Inflammasome-Mediated Diseases
| Syndrome | Gene / Pathway | Key Features | Preferred Agent |
|---|---|---|---|
| PAPA | PSTPIP1 | Pyogenic arthritis, pyoderma gangrenosum, acne | Anakinra or IL-6 inhibitor |
| DADA2 | CECR1 (ADA2) | Livedo, early-onset lacunar strokes, vasculitis, immunodeficiency | Anti-TNF (etanercept/adalimumab) |
| DIRA | IL1RN | Neonatal-onset sterile multifocal osteomyelitis, periostitis, pustulosis | Anakinra (replaces endogenous IL-1Ra) |
| HA20 | OTULIN | Early-onset Behçet-like disease; oral/genital ulcers, fever | Anakinra or anti-TNF |
IL-1 Inhibitors — Comparison
Anakinra
Kineret® · IL-1Ra (receptor antagonist)
Dose
100 mg SC daily (adults); 1–2 mg/kg/day SC (paeds)
Half-life
4–6 hours (short-acting)
Key advantage
Rapid onset; can be used as diagnostic trial in AOSD
Key side effect
Injection-site reactions (~70%); neutropenia
PBS status
⚠ PBS Authority Required
Canakinumab
Ilaris® · Anti-IL-1β monoclonal antibody
Dose
150 mg SC q8w (CAPS); 2–4 mg/kg q4–8w (paeds)
Half-life
26 days (long-acting)
Key advantage
Convenient dosing; approved for CAPS, FMF, TRAPS, HIDS, SJIA
Key side effect
Upper respiratory infections; risk of hepatitis B reactivation — screen pre-treatment
PBS status
⚠ PBS Authority Required
Infection screening before IL-1 blockade: Tuberculosis (Quantiferon-Gold), hepatitis B/C serology, HIV. Live vaccines contraindicated during treatment. Inactivated vaccines may have reduced immunogenicity.
Genetic Testing
Genetic confirmation is increasingly essential for precision therapy. Australian resources:
✔ Available
MEFV gene sequencing
Single-gene test; MBS item 73288. Turnaround: 4–8 weeks. Available via public genetics services in all states.
✔ Available
NLRP3 gene sequencing
For CAPS suspicion. Mosaicism may require deep sequencing of multiple tissues (skin biopsy).
✔ Available
Autoinflammatory NGS panel
Multi-gene panel (MEFV, NLRP3, TNFRSF1A, MVK, PSTPIP1, CECR1, IL1RN, MEFV, ADA2, etc.). Turnaround: 6–12 weeks. Available at Victorian Clinical Genetics Services (VCGS), SA Pathology, Sonic Genetics.
→ Referral
Whole exome/genome sequencing (WES/WGS)
For panel-negative patients with high clinical suspicion. Referral to clinical genetics service or undiagnosed diseases programme. Consider via Australian Genomics Health Alliance.
Practical Guidance
- Discuss genetic testing with a clinical geneticist or genetic counsellor pre-test
- Genetic results require phenotypic correlation — variants of uncertain significance (VUS) are common
- Inform Medicare genetics referral (GP referral → specialist → genetics service)
- Presymptomatic testing in at-risk family members for autosomal-dominant conditions (TRAPS, CAPS) should follow NHRMC guidelines
- Store DNA samples for future re-analysis as gene panels expand
Special Populations
Pregnancy
Colchicine
Safe in pregnancy (extensive FMF data); does not increase teratogenic risk. Continue at usual dose. Compatible with breastfeeding.
Anakinra
Limited data; considered if disease uncontrolled. Category B3. Continue only if benefit > risk. Breastfeeding: avoid or discontinue.
Canakinumab
Insufficient data; generally avoided in pregnancy. Discontinue ≥4 months before planned conception.
Paediatrics
NOMID/CINCA
Requires early IL-1 blockade (anakinra from neonatal period). Refer to tertiary paediatric rheumatology (RCH Melbourne, Westmead Children's).
FMF (children)
Colchicine from diagnosis. Weight-based dosing (see FMF section). Monitor for growth and school attendance.
Canakinumab (paeds)
2 mg/kg (≥7.5 kg) to 4 mg/kg SC every 4–8 weeks. Vaccination schedule should be completed before starting.
Renal Impairment
Colchicine
Dose reduce 50% if eGFR <30 mL/min. Avoid in dialysis if possible. Monitor for myopathy/neuropathy.
Anakinra / Canakinumab
No formal dose adjustment; monitor for infection in advanced CKD (immunosuppression risk). Monitor LFTs/FBC fortnightly initially.
Immunocompromised
IL-1 inhibitors
Increased serious infection risk. Screen for latent TB, hepatitis B before initiation. Avoid live vaccines. Monitor FBC fortnightly initially.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
📚 References
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