Autoinflammatory disease and Still disease

• Autoinflammatory diseases are not autoimmune diseases: the immune system attacks the body without the autoantibodies or antigen-specific T cells that define autoimmunity. Inherited fever syndromes such as familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and the cryopyrin-associated periodic syndromes (CAPS) are the classic monogenic examples.
• Adult-onset Still disease (AOSD) is now viewed as the adult counterpart of systemic juvenile idiopathic arthritis (sJIA). Together these two are the disease the 2024 EULAR/PReS guideline calls Still disease.
• Different syndromes have different rhythms: FMF attacks last 1 to 3 days, TRAPS attacks last weeks, and AOSD produces a daily spiking fever with a salmon-pink rash and high ferritin. ^[1]
• Colchicine is the anchor drug in FMF and prevents attacks in at least 95% of patients when taken continuously. IL-1 blockade is the anchor treatment for Still disease, TRAPS and CAPS; it is also used when FMF is resistant to colchicine.
• The outcome that matters most is complete control of inflammation, because persistent subclinical inflammation is what produces AA (secondary) amyloidosis, renal failure and early death. Proteinuria is checked every 6 to 12 months for this reason.

By the end of this page you should be able to:

1. Distinguish autoinflammatory from autoimmune disease and name the principal monogenic syndromes.
2. Explain FMF, TRAPS and CAPS from their genetic lesion to their clinical phenotype, and recognise each by the length of its fever episodes.
3. Make a working diagnosis of adult-onset Still disease, use the Yamaguchi criteria and name the MAS warning signs.
4. Plan investigations, including genetic testing, inflammatory markers, ferritin, IL-18/S100 proteins and amyloidosis screening.
5. Prescribe and titrate colchicine, choose and dose IL-1 blocking therapy, and state which patients need it for the brain or eye.
6. Detect AA amyloidosis early and explain why colchicine must be continued even when a biologic is added.

Innate immunity is the body's alarm system. It senses danger through pattern recognition receptors and inflammasomes, and responds with rapid bursts of interleukin-1 (IL-1), IL-6 and tumour necrosis factor (TNF). Autoinflammatory diseases are conditions in which this alarm fires repeatedly without infection and, crucially, without the autoantibodies or autoreactive lymphocytes that define autoimmune disease. The inherited forms are usually monogenic: a mutation in a single gene encoding a component of the IL-1 pathway produces a recognisable pattern of periodic fever.

Autoimmune disease can coexist with autoinflammation, and boundaries blur. Still disease (sJIA/AOSD) is best described as a non-familial, probably polygenic, systemic autoinflammatory disorder in which adaptive immunity also participates, particularly in the chronic arthritis phase.

A clinically useful classification is:

• Monogenic IL-1-driven diseases (mutated gene → overactive inflammasome or cytokine receptor): FMF (MEFV), TRAPS (TNFRSF1A), CAPS (NLRP3), mevalonate kinase deficiency/MKD (MVK), deficiency of the IL-1 receptor antagonist/DIRA (IL1RN). These are treated primarily as IL-1 diseases.
• Non-familial systemic autoinflammatory disease: Still disease (sJIA in children, AOSD in adults), including its macrophage activation syndrome (MAS) complication.
• Other inherited periodic fevers: PFAPA (periodic fever with aphthous stomatitis, pharyngitis and adenitis), Schnitzler syndrome (acquired, associated with IgM monoclonal protein), and monogenic syndromes outside the IL-1 axis such as Blau syndrome and PAPA syndrome.

This page concentrates on what a medical student is expected to master: FMF, TRAPS, CAPS, Still disease, colchicine, IL-1 inhibition and the amyloidosis risk shared by all of them.

Numbers for these disorders are global and approximate. FMF is the commonest monogenic periodic fever worldwide. It is thought to affect between 1 in 250 and 1 in 500 people of Sephardic Jewish origin and about 1 in 1000 people in Turkey. ^[1] TRAPS is very rare, with an estimated prevalence of about 1 in a million in Europe. ^[1]

Most monogenic syndromes begin in childhood: CAPS often from birth or early infancy, TRAPS usually before the age of 4 years, and MKD in the first year of life. AOSD is an adult diagnosis; the age threshold of 16 years that separates it from sJIA was originally arbitrary and the two conditions are now regarded as one disease. ^{[2] [1][5]}

Because sJIA incidence peaks below the age of 6 years while remaining stable in adolescents and young adults, the bimodal impression is partly an artefact of how paediatric and adult services are organised. ^[2]

FMF is an autosomal recessive disease caused by mutations in MEFV, which encodes pyrin. About 85% of patients carry changes in both copies of the gene; 14 to 25% of people with a clinical diagnosis have only one identified mutation, while as many as 1 in 4 healthy individuals in some eastern Mediterranean populations carry a single mutation. ^[1] This illustrates two points: FMF is a clinical diagnosis first, and genetic testing is an aid to it rather than a substitute.

TRAPS is an autosomal dominant disease caused by mutations in TNFRSF1A, encoding tumour necrosis factor receptor 1; because only one abnormal copy is needed, families are common. ^[1]

CAPS is an autosomal dominant (or de novo) gain-of-function disease of NLRP3, encoding cryopyrin, a sensor of the NLRP3 inflammasome. About 75% of patients with the milder phenotypes have affected relatives, while severe disease is usually due to new mutations. ^[1]

Still disease has no single gene. It behaves like a systemic autoinflammatory disorder, with innate immune cytokine overproduction and HLA associations that differ between children and adults. ^[5] Triggers are unknown; infections are suspected but unproven.

Risk factors for monogenic disease are family history, ancestry consistent with the founder populations, and (for FMF) eastern Mediterranean origin. There is no known modifiable risk factor.

MEFV and pyrin. Pyrin is part of a complex that senses the cytoskeleton and restrains the pyrin inflammasome. Hypomorphic mutations allow pyrin to form an inflammasome that cleaves pro-IL-1β and pro-IL-18, while also destabilising microtubules. The result is sudden, massive IL-1β release, which explains the abrupt onset, the short attack, the neutrophilia and the serositis of FMF. Colchicine binds tubulin, the building block of microtubules, and thereby suppresses both the pyrin inflammasome and neutrophil mobility. This is why one drug treats the attack and its long-term amyloid risk.

TNFRSF1A and TRAPS. Mutant TNF receptor 1 folds abnormally and accumulates in the endoplasmic reticulum. Soluble receptor, the normal brake on circulating TNF, is reduced, while endoplasmic reticulum stress drives inflammatory signalling. The fever therefore lasts much longer than in FMF and inflammation can be almost continuous in a third of patients. ^[1]

NLRP3 and CAPS. Gain-of-function NLRP3 variants assemble the cryopyrin inflammasome inappropriately, so IL-1β is produced in the cold, or continuously in the brain, eye and ear. The clinical spectrum runs from cold-triggered urticaria (familial cold autoinflammatory syndrome, FCAS) to the daily rash, hearing loss and amyloid risk of Muckle-Wells syndrome (MWS) to the severe neonatal brain and bone disease of CINCA/NOMID (chronic infantile neurological, cutaneous and articular syndrome / neonatal-onset multisystem inflammatory disease). ^[1][3]

Still disease. IL-1β, IL-6 and IL-18 are over-produced, probably secondary to inflammasome dysregulation. The signature is a spiking quotidian fever, neutrophilic leucocytosis, and ferritin levels far out of proportion to other inflammatory diseases. The natural history includes a window of opportunity early after onset, after which a chronic arthritis phase may develop. ^[2][5]

Why amyloidosis occurs. Serum amyloid A (SAA) is an acute phase reactant produced in response to IL-1, IL-6 and TNF. When inflammation is continuous, or even subclinical, SAA remains raised for years. It misfolds into AA fibrils that deposit in kidney, liver, gut, thyroid and spleen. The kidney is the site that kills patients: proteinuria, nephrotic syndrome, renal failure. This is the complication every treatment target in autoinflammatory disease is designed to prevent.

Attacks occur irregularly and can be triggered by minor physical or emotional stress, the menstrual cycle or changes in diet. ^[1] They usually last 1 to 3 days. ^[1] Severe abdominal pain, indistinguishable from an acute abdomen, occurs in 85% of patients; pleuritic chest pain, usually unilateral and worse on coughing, in 40%; and exertional calf muscle pain between attacks in 20% of affected children. ^[1] A characteristic rash around the ankles occurs in 20%. ^[1] Fever and neutrophilia accompany every attack; imaging is usually normal, which is a clue that the pain is from serositis rather than infection.

The diagnosis is clinical, supported by the response to colchicine, and corroborated by genetics where testing is available. Criteria sets (Tel Hashomer and others) exist as memory aids. Genetic testing is particularly useful in doubtful cases.

Colchicine is the anchor: continuous low-dose treatment prevents or substantially reduces attacks in at least 95% of patients and is vital in anyone who has already developed AA amyloidosis. ^[1] It is generally very well tolerated in children and adults. ^[1]

Dosing is individualised and should be taken from the current EULAR/PReS FMF guidance and your local formulary. The 2024 EULAR/PReS FMF guideline sets explicit titration and biologic steps for resistant disease. In routine terms:

• Introduce colchicine gradually; diarrhoea is the commonest limiting side effect and is reduced by slow escalation and, if needed, temporary withdrawal of milk from the diet. ^[1]
• Titrate to the control of attacks and of subclinical inflammation, monitored clinically and by CRP or SAA.
• During an uncomplicated attack the usual dose is taken in full; additional simple analgesia or an NSAID can be added.
• Colchicine is continued during conception, pregnancy and lactation; there is no evidence that it causes infertility or birth defects, and nursing mothers can take it. ^[1]
• Toxicity rises sharply when renal function is reduced and in overdose; drug interactions are the main avoidable cause of harm.

Colchicine is licensed by the US Food and Drug Administration for FMF from the age of 4 years upward. ^[1]

Adherent patients who continue to have recurrent attacks despite the maximum tolerated dose are classified as resistant; an IL-1 inhibitor (anakinra or canakinumab) is added rather than substituted, because continuing colchicine reduces amyloid risk.

TRAPS affects about 1 person in a million in Europe and usually presents before the age of 4 years. ^[1] Fever episodes last weeks, and in a third of patients symptoms are nearly continuous. ^[1] More than 95% have fever, 80% have limb pains that migrate toward the trunk, 80% have abdominal pain, and 70% have rash. ^[1] Periorbital oedema and myalgia are characteristic clues. ^[3] Genetic testing is necessary for diagnosis. ^[1]

Acute attacks can be aborted by high-dose corticosteroids, but these do not prevent recurrence. ^[1] In more severe disease, maintenance therapy with IL-1 blockade, or sometimes the TNF decoy receptor etanercept, is used, although etanercept is not licensed for TRAPS. ^[3] NSAIDs may give symptom relief during episodes. ^[3] Patients with severe disease and high-inflammatory variants carry the highest amyloid risk in TRAPS. ^[3]

CAPS is the clinical spectrum of activating NLRP3 mutations:

• Familial cold autoinflammatory syndrome (FCAS): mild, with cold- or stress-triggered fever, urticarial rash and arthralgia.
• Muckle-Wells syndrome (MWS): moderate, with everyday or episodic rash, fever and arthralgia, sensorineural hearing loss in up to 40%, and amyloid risk.
• CINCA/NOMID: severe neonatal disease with chronic meningitis, papilloedema, hearing and vision loss, epiphyseal overgrowth and deforming arthropathy. Untreated, early death can occur.

Diagnostic clues include an urticaria-like non-itchy rash, cold-triggered episodes, sensorineural hearing loss, chronic aseptic meningitis, skeletal abnormalities and a positive family history. ^[3] The EULAR/ACR points to consider recommend NGS, or Sanger sequencing of NLRP3 when suspicion is strong, with deep sequencing for somatic mosaicism in severe unexpected cases. ^[3]

IL-1 blockade is the standard of care, and includes anakinra, canakinumab and rilonacept. ^[3] Treatment should start early to prevent organ damage. ^[3] Anakinra penetrates the central nervous system better and may be the most effective choice for brain disease. ^[3] In practice, canakinumab is conveniently given as an injection under the skin every 8 weeks. ^[1] Higher or more frequent dosing is often needed in severe or very young disease. ^[3]

AOSD and sJIA are the same disease. ^{[2] [5]} The 2024 EULAR/PReS guideline calls it Still disease and defines CID (clinically inactive disease) as absence of clinical features with normal ESR or CRP, and remission as CID maintained for at least 6 months. ^{[2] [4]}

The operational definition of Still disease is deliberately broad so that treatment can start early: ^[2]

• Fever that is spiking and reaches 39 degrees Celsius or higher for at least 7 days.
• Rash that is transient, often coinciding with fever spikes, on the trunk, classically a salmon-pink, maculopapular, non-pruritic rash; urticarial rashes can also fit.
• Musculoskeletal involvement usually present as arthralgia or myalgia; overt arthritis appears in about half of patients and may be delayed by a median of 1 month after onset, so arthritis is supportive but not required for diagnosis. ^[2]
• High inflammation: neutrophilic leucocytosis, raised CRP and ESR, and very high ferritin.
• Other features: sore throat, myalgia, weight loss, serositis, lymphadenopathy, hepatosplenomegaly and abnormal liver tests.

Because no single feature is specific, other causes must be excluded before accepting the diagnosis: infection, malignancy (particularly lymphoma), other connective tissue diseases and the monogenic autoinflammatory syndromes. ^[2] Yamaguchi criteria (1992) remain the validated adult set, requiring 5 of 9 items with at least 2 of the first 4, with a sensitivity of 96.3% and specificity of 98.2% in adults, rising to sensitivity 100% and specificity 97.1% when ferritin is added. ^[2] Fautrel criteria, which include glycosylated ferritin at 20% or less, can be used where that assay is available. ^[2]

Sore throat and myalgia are common. Ferritin should be markedly raised, often far higher than in infection or other inflammatory states. IL-18 and S100 proteins (calprotectin among them) strongly support the diagnosis when raised, but validated cut-offs do not yet exist, so they are still mainly used in specialist centres. ^[2]

MAS is the life-threatening complication of Still disease. It occurs in up to 23% of AOSD patients. ^[4] Think of it in a patient with persistent fever, splenomegaly, rising ferritin, inappropriately low blood counts, abnormal liver function, intravascular coagulation and rising triglycerides. ^[2] It is an emergency: high-dose glucocorticoids plus an IL-1 inhibitor, ciclosporin and, in severe cases, an interferon-gamma blocking agent. ^[2]

The philosophy is treat-to-target: avoid prolonged glucocorticoid exposure; start an IL-1 or IL-6 inhibitor as soon as the diagnosis is made; reach clinically inactive disease; withdraw glucocorticoids; then maintain for 3 to 6 months before tapering biologics.

Targets from the 2024 EULAR/PReS guideline are: ^[2]

• Day 7: fever resolved and CRP reduced by more than 50%. ^[2]
• Week 4: no fever, active joint count reduced by more than 50%, normal CRP, and physician and patient (or parent) global assessment below 20 on a 0 to 100 visual analogue scale. ^[2]
• Month 3: clinically inactive disease on glucocorticoids below 0.1 mg per kg per day in adults (0.2 in children). ^[2]
• Month 6: inactive disease off glucocorticoids. Remission is 6 months of inactive disease. ^[2]

High-dose glucocorticoids (prednisone equivalent 1 mg per kg per day or more) are more effective than low dose at onset, particularly in impending MAS or severe pericarditis, but prolonged exposure must be avoided. ^[2]

• NSAIDs for mild or suspected disease.
• Glucocorticoids: short course for mild disease; 0.8 to 1.0 mg per kg per day of prednisone equivalent for severe disease; observers in the Dutch expert consensus achieved higher 6-month remission with high-dose (65%) than low-dose (23%) glucocorticoid, but MAS was seen more often in the low-dose group. ^{[4] [2]}
• IL-1 blockade: the initial dose of anakinra given subcutaneously ranges from 100 to 400 mg daily depending on severity; over 100 mg daily is off-label; intravenous anakinra 200 to 400 mg daily is used in rapidly progressive disease; children may receive up to 8 mg per kg. ^[4] Canakinumab is given subcutaneously, and rilonacept weekly.
• IL-6 blockade (tocilizumab): an option for glucocorticoid-resistant or -dependent disease, and often preferred when arthritis dominates, although comparative trials are lacking. ^[4]
• Methotrexate (MTX) helps arthritis-predominant disease; TNF blockade is reserved for patients without systemic symptoms after IL-1 and IL-6 failure.
• Biologic tapering: maintain 3 to 6 months of inactive disease off glucocorticoids before any taper; taper canakinumab by interval extension.

Response data come from retrospective practice. Anti-IL-1 therapy in refractory AOSD has shown effectiveness from 50 to 100% (median 83.3%), remission from 22.2 to 100% (median 70%) and treatment failure from 0 to 50% (median 16.7%). ^[5] The response is rapid and sustained, and steroid sparing is substantial: 17 to 48% of patients come off corticosteroids altogether. ^[5] Higher rates of inactive disease off glucocorticoids are seen with early initiation, which supports the window-of-opportunity approach. ^{[5] [4]}

Anakinra has the most reassuring safety profile among the IL-1 inhibitors, though injection-site reactions occur in 10 to 66.6% of patients and reversible hepatotoxicity has been reported. ^[5] Serious adverse events in the EULAR Still disease pooled data were 22.6 per 100 patient-years for all IL-1 inhibitors combined and 36.5 for tocilizumab; MAS occurred at 3.2 and 2.7 per 100 patient-years respectively. ^[2]

Colchicine is licensed for FMF from the age of 4 years. ^[1] Key teaching points about its mechanism and use:

• Mechanism: binds tubulin, blocks microtubule polymerisation. This inhibits both pyrin inflammasome assembly and neutrophil chemotaxis, and is anti-inflammatory at the very low doses used in autoinflammatory disease.
• Pharmacokinetic traps: colchicine is cleared by CYP3A4 and P-glycoprotein, so inhibitors such as clarithromycin, cyclosporin, diltiazem, ritonavir and grapefruit can precipitate fatal toxicity; it accumulates in renal impairment.
• Toxicity: diarrhoea, nausea, abdominal pain, vitamin B12 malabsorption and myopathy; rare, but dangerous, bone marrow suppression in excess.
• Monitoring: blood counts and liver enzymes are checked and the dose reduced if they rise; in reduced renal function, toxicity is more likely and serum creatine kinase and symptoms of colchicine poisoning are watched closely.
• Drug interactions need checking every time a new drug is prescribed.

Three IL-1 blocking drugs dominate practice:

• Anakinra: a recombinant IL-1 receptor antagonist, given daily; blocks both IL-1α and IL-1β, with better central nervous system penetration. Its short half-life makes it the drug of choice in suspected sepsis and in life-threatening rapidly progressing Still disease, because it interferes least with the diagnostic process. ^{[4] [3] [5]}
• Canakinumab: a human monoclonal antibody against IL-1β with a long half-life, given every 4 to 8 weeks; approved for AOSD and SJIA in Europe, and for CAPS, TRAPS and MKD in both Europe and the USA.
• Rilonacept: an IL-1 trap fusion protein, given weekly, effective in CAPS; it is not licensed for Still disease in Europe or the USA.

Approvals differ by region and age, so the drug that is actually available locally determines selection as much as pathophysiology. When bacterial infection remains on the differential diagnosis, or when central nervous system disease needs rapid control, anakinra is usually preferred; when compliance or chronic maintenance is the issue, longer-acting agents are favoured.

Tapering has its own protocol: at least 3 to 6 months of inactive disease off glucocorticoids before starting; progressive tapering by 3- to 6-month steps, either dose reduction or interval prolongation. A coherent plan is written at the outset so that patients and families know what "remission" means for them. ^[2]

AA amyloidosis is the feared complication. It develops from months to years of uncontrolled or subclinical inflammation. In FMF, untreated patients still develop it; with continuous colchicine, attack-free and inflammation-free patients usually do not. In CAPS, TRAPS and MKD, early IL-1 blockade makes amyloidosis far less common. In AOSD, amyloidosis is rare but documented. ^[5]

Clinical rules:

• Ask about and test for proteinuria and microalbuminuria regularly: every visit in long-standing untreated disease, and every 6 to 12 months routinely in IL-1 mediated syndromes. ^[3]

• In FMF with amyloidosis, treatment is intensified with the maximum tolerated dose of colchicine and biologics as required.

• In TRAPS, cysteine mutations predict high amyloid risk; in CAPS, severe persistent disease does likewise.

• Once established, AA amyloidosis is managed by a specialist amyloid centre, with the same treatment goal of completely suppressing systemic inflammation; regression of proteinuria can be seen when inflammation is fully controlled.

Use the attack length and associated features to orient yourself before the genetics come back.

The differential diagnosis of an adult with recurrent fever and rash is broad and includes adult-onset Still disease, infection, malignancy and autoimmune disease. The monogenic syndromes overlap with each other, which is why classification algorithms separate mild migratory erythematous rashes from the cold-triggered urticaria of CAPS.

No blood test diagnoses a monogenic periodic fever on its own. The work-up should be structured:

• During an attack: CRP, ESR, full blood count, fibrinogen, SAA; blood and urine cultures if infection is possible; liver tests; ferritin.
• Between attacks: if possible, repeat markers to demonstrate subclinical inflammation; in FMF, a completely normal baseline is compatible with inactive disease.
• Genetic testing: NGS for CAPS, TRAPS, MKD and DIRA; Sanger sequencing of MEFV for FMF. ^[3]
• Biomarkers: IL-18 and S100 proteins support both Still disease and monogenic IL-1 disease; glycosylated ferritin at 20% or less is part of the Fautrel criteria. ^[2]
• Amyloidosis screening: urine dipstick for protein, microalbuminuria, serum creatinine, plus SAA if available. ^[3]
• Organ-specific: audiogram and ophthalmology in CAPS; lumbar puncture and head imaging if central nervous system disease is suspected; chest and limb imaging in DIRA. ^[3]
• Still disease: scoring of Yamaguchi or Fautrel criteria, which require exclusion of infection, malignancy and other rheumatic disease. ^{[2] [4]}

• Pregnancy: colchicine is continued through conception, pregnancy and breastfeeding, with no evidence of teratogenicity in standard doses. ^[1] Data on IL-1 blockers in pregnancy are based on case series; any biologic is managed jointly by rheumatology, obstetrics and pharmacy.
• Children with a new diagnosis: monogenic syndromes usually require specialist centres; early IL-1 blockade in CAPS prevents deafness and brain damage. ^[3]
• Older adults: AOSD can present for the first time in older age and remains a diagnosis of exclusion; comorbidity shapes drug choice.
• Immunocompromised patients: MAS risk is increased; vaccination should be brought up to date before IL-1 blockade, including pneumococcal and influenza vaccination in line with local policy. ^[3]

• The single most useful test is the attack pattern described by the patient, plus CRP measured during symptoms. Genetic testing is ideal but unreachable in many settings; a documented response to colchicine is itself diagnostically informative.
• Empirical colchicine at low, safely titrated doses is reasonable when attacks are typical of FMF and no other diagnosis is likely; follow the local formulary for renal or hepatic impairment.
• Still disease without early access to biologics can be treated with glucocorticoids and methotrexate as a bridge, with referral to a centre that can provide IL-1 blockade.
• AA amyloidosis in low-resource settings presents late; a urine dipstick and a creatinine test are cheap and preventable if done regularly.
• Monogenic severe CAPS and TRAPS need referral; canakinumab is expensive and access is uneven between countries, which is the single most common cause of persistent disease in these syndromes.

• Attack-related: peritonitis mimicking an acute abdomen, pleurisy, orchitis, arthritis; in CAPS, permanent sensorineural hearing loss, aseptic meningitis and visual impairment.
• Macrophage activation syndrome in Still disease (up to 23% of adults). ^[4]
• AA amyloidosis with renal failure: the most serious long-term complication across all these diseases. ^[1]
• Treatment-related: infection (respiratory, skin), injection-site reactions (10 to 66.6% with anakinra), corticosteroid toxicity.
• Rare: ILD (interstitial lung disease) in a subset of children with Still disease with NLRP3 and HLA associations; this is a specialist topic.

Prognosis is transformed by early treatment. With consistent colchicine, FMF patients usually lead normal lives and amyloidosis is prevented in most. ^[1] IL-1 blockade in CAPS, TRAPS and Still disease has turned previously fatal or disabling childhood disease into manageable chronic disease, and drug-free remission is realistic for many who start treatment early. ^{[2] [3]} The residual problems are late diagnosis, non-adherence, diagnostic uncertainty in low-penetrance variants, and access to biologics.

• Autoinflammatory disease is innate-immunity overactivity; autoimmune disease is adaptive-immunity dysregulation. The two can overlap.
• FMF: recessive MEFV disease; attacks of 1 to 3 days with serositis; colchicine prevents attacks in at least 95% and protects against amyloid; add IL-1 blockade only after resistance is proven.
• TRAPS: dominant TNFRSF1A disease; fever for weeks; corticosteroids abort attacks, IL-1 blockade prevents them; cysteine mutations signal high amyloid risk.
• CAPS: spectrum of NLRP3 gain-of-function; cold-triggered, daily, or neonatal-severe; IL-1 blockade is standard and brain disease may need anakinra.
• Still disease: AOSD and sJIA are one disease; spiking fever of at least 7 days at 39 degrees Celsius or more, salmon-pink rash, sore throat, arthritis, very high ferritin; MAS in up to 23%.
• Yamaguchi criteria need 5 of 9 items with at least 2 of the first 4 and have 96.3% sensitivity and 98.2% specificity in adults. ^[2]
• Treat to target: day 7 fever resolved and CRP down more than 50%; week 4 no fever, joints down more than 50%, global under 20/100; month 3 inactive on less than 0.1 mg/kg/day glucocorticoid; month 6 inactive off glucocorticoids.
• High initial glucocorticoid dosing (1 mg per kg per day or more) is more effective than low dose in severe Still disease.
• IL-1 blockers give 50 to 100% (median 83.3%) effectiveness in refractory AOSD, with 22.2 to 100% (median 70%) remission. ^[5]
• Anakinra 100 to 400 mg subcutaneously daily (200 to 400 mg intravenously in rapid progression) is the usual first IL-1 blocker; escalate within 2 days if there is no response. ^[4]
• AA amyloidosis is prevented by complete control of inflammation; check urine protein every 6 to 12 months in chronic IL-1 disease and intensify treatment if it appears.
• Colchicine is the one drug that treats FMF at its root and is vital in pregnancy-associated disease; its drug interactions are dangerous.
• Related topics: gout, vasculitis fever of unknown origin, inflammatory arthritis, renal amyloidosis.

Autoinflammatory disease and Still disease relates to gout and crystal arthritis, rheumatoid and other inflammatory arthritides, sepsis and fever of unknown origin, renal amyloidosis and nephrotic syndrome, haemophagocytic lymphohistiocytosis and macrophage activation syndrome, and pregnancy in systemic autoimmune disease. It also underpins selection of biologic therapy in rheumatology.