Adult-Onset Still's Disease

Meet the patient

A 24-year-old teacher is referred in as "pyrexia of unknown origin, ?lymphoma". For ten evenings her temperature has spiked high, settling back towards normal by dawn; she is well between spikes. The on-call registrar glimpsed a faint salmon-pink rash over her trunk at the height of a fever and wrote "drug reaction — review with GP". Her sore throat has never settled. Ferritin returns markedly raised, ANA and RF negative, with a leucocytosis.^[1][2]

Two exam questions are now live, and they are the two that decide every Still's case: is this really Still's — or the lymphoma or endocarditis she was referred in as? and is she about to tip into macrophage activation syndrome? Hold both questions and the rest of the page slots in around them.^[1][6]

The tetrad — and why you must examine during the spike

Still's answers are written in the tetrad: quotidian spiking fever, an evanescent salmon-pink rash, arthritis, and a sore throat. Add a ferritin through the roof and negative autoantibodies, and you have the exam answer — but the devil is in the timing of each feature.^[1][2]

1. Quotidian spiking fever — the spike comes in the late afternoon or evening, usually 39 °C or higher (most over 39.5 °C), and dips back towards normal by morning so the patient is often well between spikes. A fever that is unremitting and never dips should make you doubt the diagnosis.
2. Evanescent salmon-pink rash — non-pruritic, macular or maculopapular, salmon-pink, over the trunk, proximal limbs and pressure/rubbing areas (Koebner). It appears with the fever and fades without scarring as the fever settles — so it is constantly missed unless you examine during a spike, or ask the family to photograph it.
3. Arthritis or arthralgia — usually polyarticular and symmetric, hitting wrists, knees, ankles, the MCP and PIP joints, shoulders, elbows and hips. In the chronic articular pattern it turns erosive and deforming, and can look exactly like rheumatoid arthritis except for the negative RF/anti-CCP and the preceding systemic illness.
4. Sore throat — a persistent, non-exudative pharyngitis in over 90 percent of patients; the most under-valued minor criterion, and in the right context a strong steer towards Still's.^[1]

Systemic features beyond the tetrad: marked malaise, fatigue and weight loss; severe myalgia; generalised (often cervical) lymphadenopathy; splenomegaly and hepatomegaly; abdominal pain from mesenteric nodes or serositis; and serositis — pleuritis and pericarditis are the common cardiopulmonary signs, while myocarditis, tamponade, pleural effusion, interstitial pneumonitis and ARDS are the rare, lethal ones.^[2][6]

The lab pattern is as diagnostic as the clinical picture: ferritin typically higher than in other autoimmune, inflammatory, infectious or neoplastic diseases (mean 4752 μg/L in one multicenter series), a leucocytosis (a Yamaguchi major criterion), raised ESR and CRP, negative ANA and RF (a Yamaguchi minor criterion), liver dysfunction (another Yamaguchi minor criterion), and a glycosylated ferritin fraction of 20 percent or under.^[2][3][13]

Atypical presentations — the ones that bite: articular disease mimicking rheumatoid arthritis (but RF/anti-CCP negative); a fever of unknown origin with no rash (because no one examined during a spike); an older patient presenting as a FUO; acute liver injury masquerading as viral or drug-induced hepatitis; myocarditis or tamponade from serositis; and the dramatic debut of macrophage activation syndrome as the very first manifestation.^[1]

Autoinflammatory, not autoimmune — the cytokine map

Still's sits on the autoinflammatory side of the immune fence, and that single fact decides your biologic. There is no high-titre adaptive autoantibody response — which is why ANA and RF are negative and why the disease melts to cytokine-blocking drugs (IL-1, IL-6, IL-18) rather than to B-cell depletion.^[1][2][9]

Activated macrophages, neutrophils and natural killer cells fire an innate cytokine storm of IL-1β, IL-6, IL-18, TNF-α and interferon-γ (IFN-γ), with the IFN-γ signature loudest in the most severe disease. Each cytokine maps onto a clinical feature and a drug — memorise the map and you can answer any Still's question from first principles.^[1]

The cytokine map, read as a treatment chart:^[1]

• IL-1β — one of the pro-inflammatory cytokines with a major role in AOSD pathogenesis and management; IL-1 inhibitors (anakinra, canakinumab) are required mainly in patients refractory to traditional therapy and are recommended for MAS in the 2024 EULAR/PReS guidelines.^[5][7]
• IL-6 — another central cytokine; the anti-IL-6 receptor antibody tocilizumab is effective in glucocorticoid-refractory adult Still's disease.^[8][9]
• IL-18 — implicated, alongside IL-1 and IL-6, in disease onset and progression, and in the pathogenesis of Still's disease and MAS.^[1][6]
• IFN-γ — interferon-γ antagonism has evidence specifically in MAS, and the interferon signature is implicated in Still's pathogenesis; JAK inhibition is an emerging strategy in refractory disease.^[5][6]

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^[1]

Consultant confession: when a Still's patient defervesces soon after the first IL-1 blocker dose, that is not a placebo effect — it is IL-1β being switched off at source. Matching the drug to the cytokine is the whole logic of treatment.^[7]

Three patterns, one emergency

The clinical course — not the presentation — sorts Still's into three patterns, and the pattern picks the drug and the prognosis. Learn to name the pattern early, because a monocyclic patient you can stop treating, while a chronic articular patient you cannot.^[2][6]

• Monocyclic (about a third): a single systemic episode that fully remits within a year (usually within nine months) and does not recur. The best prognosis — often NSAIDs and a short, tapering steroid course is all it takes.
• Polycyclic, or relapsing-remitting (about a fifth): recurrent systemic flares separated by remissions of variable length; between flares the patient is well and the markers normalise. Joints are usually spared because the flares are systemic, not relentlessly articular.
• Chronic articular (about a third to a half): persistent polyarthritis that dominates the course and does the structural damage — erosive, deforming disease of the wrists, knees, ankles and the small joints of the hands. This is the pattern that needs conventional synthetic DMARDs, and IL-6 blockade (tocilizumab) is used for glucocorticoid-refractory disease.^[1][9]

The fourth, feared pattern is Still's complicated by macrophage activation syndrome (secondary HLH) — a medical emergency that can land on any of the three patterns, most often early in the course or during a flare.^[2]

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^[1]

How rare — and why rarity is the clue

Still's is genuinely rare, and that rarity is itself the diagnostic clue: a common disease presenting with spiking fever and a high ferritin is far more likely to be infection or lymphoma than Still's, so the burden of proof sits with you.^[1]

• Incidence: about 0.16 to 0.4 new cases per 100,000 adults per year; prevalence roughly 1 to 34 per million depending on the population. Reported worldwide, with no definite ethnic predilection.
• Age: a characteristic bimodal distribution — a first peak at 15 to 25 years and a second at 36 to 46 years; most patients sit between 16 and 35.
• Sex: roughly equal, with a slight female preponderance (M = F in most series).
• Genetics: associations with HLA-DRB1 alleles and, in some populations, HLA-B17 and HLA-B35 — the footprint of a polygenic innate-immune disorder, not a classic HLA-linked autoimmune disease.
• Trigger: an infective or stressor stimulus in a susceptible host often precedes onset — rubella, parvovirus B19, EBV, Coxsackie, CMV, Yersinia, Chlamydia pneumoniae and Mycoplasma among others. None is causative in the Koch sense; the model is an infection igniting a dysregulated innate response that then becomes self-sustaining.
• Mortality: up to 16 percent of patients die during follow-up from AOSD-related complications; MAS is the most severe complication — reported in up to 15 percent of AOSD patients in one review and as high as 23 percent in a systematic review — and carries a high mortality rate.^[1][2]

Etymology for viva gold: George Still described the childhood form in 1897; Bywaters characterised the adult counterpart in 1971. The child and the adult share one biology, one cytokine storm, and one MAS risk — which is why paediatric rheumatology and adult rheumatology treat the same disease with the same drugs.^[9]

Exclude first, diagnose second — the classic trap

Still's is a diagnosis of exclusion, which means the differential is not a list you work down — it is the diagnostic process itself. You do not "also" rule out infection and lymphoma; the Yamaguchi criteria make exclusion a precondition for applying them.^[1][2]

The classic trap: labelling a patient Still's before you have excluded lymphoma and infective endocarditis. These are not afterthoughts — they are named Yamaguchi exclusion criteria, and missing either one is the most dangerous error in the disease.^[3]

• Infection — sepsis, endocarditis, occult abscess, disseminated TB, malaria, enteric fever. The spiking fever, leucocytosis and high markers overlap completely. Exclude with multiple blood cultures, echocardiography, and targeted imaging. A missed infected source is the cardinal error.
• Lymphoma, leukaemia, malignancy — FUO, lymphadenopathy, hepatosplenomegaly and a high ferritin all occur in lymphoma. Exclude with LDH, CT chest/abdomen/pelvis, lymph-node biopsy, and bone-marrow biopsy when cytopenias or atypical features appear.
• Systemic lupus erythematosus — fever, rash, arthritis overlap. Distinguished by positive ANA and anti-dsDNA, cytopenias (especially lymphopenia), renal disease, low complement, and a lower ferritin. Still's has negative ANA/RF and a much higher ferritin.
• Acute rheumatic fever — young patient, fever, arthritis, sore throat. Distinguished by migratory polyarthritis, carditis, raised ASO titre, evidence of preceding streptococcal infection, and the Jones criteria.
• Reactive or viral arthritis (parvovirus B19, hepatitis B and C, rubella, EBV, HIV) — preceding infection, asymmetric oligoarthritis, usually self-limited; serology sorts them out.
• Rheumatoid arthritis — symmetric small-joint polyarthritis with positive RF and anti-CCP, a lower ferritin, no evanescent rash, no quotidian fever.
• ANCA-associated vasculitis or polyarteritis nodosa — constitutional features plus organ-specific disease (renal, pulmonary, neuropathy); distinguish by ANCA, angiography, biopsy.
• Periodic fever syndromes (familial Mediterranean fever, PFAPA, TRAPS) — recurrent fevers, younger age, ethnic predilection; genetic testing of the relevant genes.
• DRESS, serum sickness, severe drug reaction — rash, fever, eosinophilia, and a clear recent drug exposure with a characteristic latency (two to eight weeks for DRESS).^[1]

The face-off — AOSD vs SLE vs lymphoma (the hyperferritinaemia differential)

A ferritin in the thousands is the single most suggestive test in Still's, but a high ferritin is never diagnostic on its own. Three diseases own the hyperferritinaemia differential, and each is a diagnosis of exclusion of the other two.^[1][2]

• Still's — ferritin typically higher than in any other autoimmune, inflammatory, infectious or neoplastic disease (mean about 4752 μg/L in one multicenter series), with a glycosylated fraction of 20 percent or under and the systemic clinical picture.^[2][13]
• MAS or secondary HLH — hyperferritinaemia is an HLH-2004 criterion and ferritin typically climbs as the syndrome evolves, with falling counts and fibrinogen; this can complicate Still's itself.^[10]
• Septic shock or severe bacterial infection — ferritin can be very high, but the clinical picture and positive cultures distinguish it.
• Lymphoma, leukaemia, disseminated malignancy — high ferritin and LDH; biopsy is diagnostic.
• Massive hepatocellular necrosis or acute liver failure — ferritin released from dying hepatocytes; the transaminases dominate.
• Hereditary haemochromatosis or iron overload — chronically high ferritin with a high transferrin saturation, not an acute febrile illness.
• Chronic alcohol misuse, metabolic dysfunction–associated steatotic liver disease, or unrelated chronic inflammation — moderate elevation, no spiking fever.

The practical rule: a ferritin typically higher than in infection, malignancy or other rheumatic disease with a spiking fever, an evanescent rash, arthritis, negative ANA/RF, and no infection or malignancy is Still's until proven otherwise — but the exclusions are mandatory, not optional.^[1][2][3]

The bedside round — build a fever-and-ferritin chart

Approach the patient as a fever of unknown origin and a diagnosis of exclusion: rule out infection first, then malignancy, then other rheumatic disease — and only then apply the classification criteria.^[1]

• Confirm the quotidian rhythm (one to two daily spikes, usually evening, over 39 °C) with a nursing temperature chart over several days — the rhythm is diagnostic information and must be documented, not assumed.
• Examine during a fever spike. The salmon-pink rash is evanescent and is reliably seen only when the patient is febrile; examine the trunk, proximal limbs and pressure areas, and ask the family to photograph it between reviews.
• Examine the throat (non-exudative pharyngitis), palpate for lymphadenopathy and hepatosplenomegaly, auscultate for a pericardial or pleural rub, and examine every joint (wrists and small hand joints most often).
• Hunt for MAS at every review: a new persistent fever with falling white cells and platelets, falling fibrinogen, and rising ferritin, LDH and transaminases converts a diagnostic puzzle into an emergency.
• Check the rash for Koebner phenomenon — linear streaks along lines of scratching or tight clothing (under waistbands, bra-straps, watch-straps) — because the rash favours areas of mild mechanical trauma.
• Listen for serositis — a pericardial or pleural rub, a pericardial effusion (muffled heart sounds, raised JVP) or a pleural effusion (reduced breath sounds at a base); serositis is common and usually silent until large.
• Build a fever-and-ferritin chart: plot temperature, CRP and ferritin daily. Still's shows a quotidian fever with parallel spikes in CRP and ferritin; MAS shows a ferritin that climbs while fibrinogen and platelets fall — the divergence is the signal.
• Do not miss the two bedside diagnoses: infective endocarditis (new murmur, splinter haemorrhages, embolic phenomena — echo and cultures) and lymphoma (hard, fixed or matted nodes, hepatosplenomegaly, night sweats — biopsy).^[1]

There is no confirmatory test — so what are you looking for?

Investigations in Still's serve two masters — to support the diagnosis and to exclude the mimics — and the second job is the more important. There is no single diagnostic test, and a normal ferritin essentially excludes active disease.^[1][2]

Supportive bloods:^[1]

• Full blood count: leucocytosis (a Yamaguchi major criterion). In MAS the counts fall — cytopenias are an HLH-2004 criterion, so a dropping platelet or white count in a febrile Still's patient is a red flag.^[3][10]
• Ferritin: typically higher than in other autoimmune, inflammatory, infectious or neoplastic diseases — in one multicenter series the mean was 4752 μg/L in AOSD versus 1571 μg/L in controls.^[2][13]
• Glycosylated ferritin: a fraction of 20 percent or under is supportive — combined with ferritin above the upper limit of normal it is 70.5 percent sensitive and 83.2 percent specific (92.9 percent specific with ferritin five times normal).^[13]
• CRP and ESR: both raised, reflecting the systemic inflammatory process; they track disease activity and monitor response.^[2]
• Liver function tests: liver dysfunction (abnormal transaminases) is a Yamaguchi minor criterion.^[3]
• ANA and RF: negative — the absence of both is a Yamaguchi minor criterion and a cardinal diagnostic feature. If positive, reconsider the diagnosis.^[3]
• In the MAS workup: cytopenias, hyperferritinaemia, and hypertriglyceridaemia and/or hypofibrinogenaemia all count towards the HLH-2004 criteria, and the H-score additionally weights AST and marrow haemophagocytosis.^[10][11]

Exclude infection: multiple blood cultures (including for fastidious organisms), urine culture, serology for HIV, hepatitis B and C, EBV, CMV, parvovirus B19, Mycoplasma, Chlamydia and Yersinia, echocardiography (exclude endocarditis), TB screen (IGRA ± chest X-ray), and a malaria film in endemic areas.^[1]

Exclude malignancy: LDH, CT chest/abdomen/pelvis, lymph-node biopsy if nodes are present, and bone-marrow biopsy if cytopenias or atypical cells appear; age-appropriate cancer screening (mammography, colonoscopy) in older patients.^[1]

MAS or secondary HLH workup (HLH-2004 criteria): the diagnosis needs either a molecular diagnosis or family history consistent with HLH, or five of eight criteria — fever, splenomegaly, cytopenias (bicytopenia), hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis, low or absent NK-cell activity, hyperferritinaemia, and high soluble interleukin-2 receptor (soluble CD25) levels. Haemophagocytosis on marrow is only one criterion of the eight — five suffice, so it is not a prerequisite.^[10]

Other tests: synovial fluid (if an effusion is tapped) is inflammatory, sterile, culture- and crystal-negative; imaging — chest X-ray and CT for serositis, lymphadenopathy and occult malignancy; ultrasound or MRI of symptomatic joints; liver ultrasound for hepatosplenomegaly. Bone-marrow biopsy excludes malignancy or demonstrates haemophagocytosis — it does not diagnose Still's itself.^[1]

Yamaguchi classification criteria — reproduced verbatim^[3]

The Yamaguchi criteria are the most widely used and the most examinable, and the rule is a frequent one-liner: five or more criteria in total, at least two major, and no exclusion criterion present.^[1]

Major criteria (4):^[1]

1. Fever of 39 °C or more, lasting one week or longer.
2. Arthralgia lasting two weeks or longer.
3. Typical rash — non-pruritic, salmon-pink, macular or maculopapular, on the trunk and extremities with the febrile phase.
4. Leucocytosis — 10 ×10⁹/L or more, with neutrophils 80 percent or more.^[1]

Minor criteria (5):^[1]

1. Sore throat.
2. Lymphadenopathy and/or splenomegaly.
3. Liver dysfunction (abnormal transaminases or LDH).
4. Negative rheumatoid factor and negative antinuclear antibody.
5. Abnormal LFTs (raised transaminases).^[1]

Exclusion criteria (mandatory): infection — especially sepsis and Epstein-Barr virus; malignancy — especially lymphoma; other rheumatic disease — especially polyarteritis nodosa and rheumatoid arthritis with extra-articular features. No exclusion criterion may be present. Yamaguchi carries a sensitivity of about 96 percent and a specificity of about 92 percent.^[3]

Fautrel criteria — the ferritin set^[4]

Fautrel is the alternative when the question is about ferritin or about criteria that need no exclusion. It is the only criteria set to include glycosylated ferritin, it overcomes the need for exclusion criteria, and on independent validation it performed with a sensitivity of 87.0 percent and a specificity of 97.8 percent.^[12]

The ferritin biology that makes Fautrel distinctive: a glycosylated fraction of 20 percent or under combined with ferritin above the upper limit of normal was 70.5 percent sensitive and 83.2 percent specific for AOSD in the original biomarker study (92.9 percent specific when ferritin was five times normal), with a mean glycosylated fraction of 15.9 percent in AOSD versus 31.5 percent in controls.^[12][13]

MAS is the resuscitation problem

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^[1]

Most Still's presentations are haemodynamically stable — the resuscitation problem is not fluids or pressors, it is recognising macrophage activation syndrome (secondary HLH). Miss it behind a "fever of the underlying disease" and the patient dies of a treatable emergency; that is the preventable harm in this disease.^[1][6]

• If MAS is suspected (new persistent fever with falling platelets and white cells, falling fibrinogen, rising ferritin and transaminases — cytopenias, hypofibrinogenaemia and hyperferritinaemia are all HLH-2004 criteria), treat it as an emergency: urgent admission, with high-dose glucocorticoids plus IL-1 inhibitors as recommended by EULAR/PReS 2024, ciclosporin and interferon-γ inhibitors for refractory disease, and the HLH-2004 etoposide–dexamethasone–ciclosporin A regimen under haematology guidance if needed; identify and treat any trigger; and support cytopenias, coagulopathy and organ failure.^[5][10][11]
• If cardiac tamponade (a large pericardial effusion with clinical compromise) or acute liver failure complicates the presentation, manage in the usual emergency fashion (pericardiocentesis; hepatology or liver-unit referral) while you initiate disease control.
• Exclude sepsis empirically even as you treat: take cultures first, give broad-spectrum antibiotics if there is any diagnostic doubt, and de-escalate once infection is ruled out. Never diagnose Still's in a patient still being treated for uncontrolled sepsis.

Macrophage activation syndrome in depth

MAS is a cytokine-driven, hyperinflammatory syndrome of uncontrolled T-cell and macrophage activation — haemophagocytosis, cytopenias, coagulopathy and multi-organ failure. In Still's the IL-18 and IFN-γ axis is the dominant driver: very high IL-18 primes cytotoxic T cells and macrophages, defective cytotoxic function stops the immune response switching off, and activated macrophages accumulate and phagocytose blood-cell precursors in the marrow. This is the same biology as primary (genetic) HLH and as MAS in sJIA.^[6][9]

Two overlapping frameworks are used. The HLH-2004 criteria (above) require five of eight items. The H-score is a weighted score of nine variables — known underlying immunosuppression, high temperature, organomegaly, triglyceride level, ferritin level, serum AST, fibrinogen level, cytopenia, and haemophagocytosis on the bone-marrow aspirate — that estimates an individual's probability of reactive haemophagocytic syndrome (in the derivation cohort, median 230 in proven cases versus 125 in negatives); it is freely available online.^[11]

Treatment of MAS is directed at the syndrome, not at confirming haemophagocytosis — marrow evidence is only one of the eight HLH-2004 criteria. The 2024 EULAR/PReS recommendation is high-dose glucocorticoids, IL-1 inhibitors, ciclosporin and interferon-γ inhibitors; for refractory secondary HLH, the HLH-2004 chemo-immunotherapy backbone (etoposide, dexamethasone and ciclosporin A upfront, with haematopoietic stem-cell transplantation in selected patients) runs under haematology guidance. Supportive care — cytopenia support, coagulation correction, trigger treatment, organ support — runs in parallel.^[5][10]

Everyone forgets: haemophagocytosis on the marrow smear is only one of the eight HLH-2004 criteria — five criteria suffice without it, so it is supportive but not a prerequisite for the diagnosis.^[10]

The treatment ladder — name the cytokine, pick the drug

Definitive treatment is stepwise and pattern-directed, treating to remission (no fever, normal markers, no active arthritis) and then tapering. The agent is chosen by severity and by whether systemic or articular features dominate.^[1][2][5]

Step 1 — Mild systemic disease (first-line). Start an NSAID for fever, rash and arthritis, with gastric protection. Add a glucocorticoid for systemic features that fail NSAIDs or are moderate at the outset — high-dosage corticosteroids are the usual first-line therapy when systemic symptoms predominate — tapering once fever and markers normalise.^[1][2]

Step 2 — Chronic articular pattern or steroid-sparing. Introduce a conventional synthetic DMARD: csDMARDs have demonstrated efficacy in controlling the articular manifestations and are the accepted choice in steroid-refractory patients.^[1][9]

Step 3 — Refractory systemic disease (the key biologic class is IL-1 inhibition). For systemic disease that fails glucocorticoids and conventional therapy, current evidence centres on IL-1 blockade:^[5][7]

• Anakinra — an IL-1 inhibitor (recombinant IL-1 receptor antagonist) with proven high efficacy and an excellent safety profile; IL-1 inhibitors are required mainly in patients refractory to traditional therapy, and the 2024 EULAR/PReS recommendations list IL-1 inhibitors among the treatments for MAS.^[5][9]
• Canakinumab (anti-IL-1β monoclonal antibody) — the only FDA-approved biologic for AOSD; in a systematic review of 99 patients, 68.7 percent achieved complete remission of systemic and arthritic manifestations, with an acceptable safety profile.^[1][7]

Step 4 — Chronic articular pattern (the first-line biologic is an IL-6 inhibitor). When chronic erosive polyarthritis dominates:^[1]

• Tocilizumab (anti-IL-6 receptor monoclonal antibody) — 8 mg/kg intravenously every two weeks — effective in glucocorticoid-refractory adult Still's disease in a randomised, double-blind, placebo-controlled phase III trial: systemic feature scores improved significantly and the glucocorticoid dose fell by 46.2 percent versus 21.0 percent on placebo, though the week-4 primary endpoint was not met.^[8]

Step 5 — Less common or refractory options. Janus kinase inhibition is an emerging option, with recent data suggesting the importance of early administration of IL-1/IL-6 antagonism or JAK inhibition; interferon-γ antagonism has evidence specifically in MAS; and refractory secondary HLH can be treated with the HLH-2004 chemo-immunotherapy backbone (etoposide, dexamethasone and ciclosporin A upfront) under haematology guidance.^[5][6][10]

Before any biologic: screen for TB (IGRA ± chest X-ray), hepatitis B and C, and HIV; ensure vaccinations are up to date (influenza, pneumococcal, hepatitis B) before starting immunosuppression; avoid live vaccines during therapy; and arrange baseline FBC, LFTs and renal function for monitoring.^[5]

The mantra

IL-1 for systemic, IL-6 for articular; MAS is the emergency. That single line decides the biologic in a treatment MCQ and the disposition in a sick patient. IL-1β drives the fever, rash and systemic inflammation (so anakinra or canakinumab); IL-6 drives the chronic synovitis and acute-phase response (so tocilizumab); and any Still's patient with falling counts and fibrinogen plus a climbing ferritin has MAS and needs IV steroids plus anakinra now.^[5][7][8]

Patterns in practice — what each course wants

Each clinical pattern pulls a different management lever, and naming the pattern early is the single most useful thing you do. A monocyclic patient you can stop treating; a chronic articular patient you cannot.^[2][6]

• Monocyclic pattern — a single systemic episode remitting within a year; NSAIDs and a short tapering steroid course; the best prognosis, and the patient can usually be told they are likely to make a full recovery. Do not over-treat with long-term biologics.
• Polycyclic (relapsing-remitting) pattern — recurrent flares separated by remissions; treat each flare with NSAIDs ± short steroid bursts, and add a DMARD or a long-acting IL-1 inhibitor (canakinumab) if flares are frequent or steroid-dependent. Joints are usually spared.
• Chronic articular pattern — persistent polyarthritis with erosive potential; this is the pattern that needs conventional synthetic DMARDs, with tocilizumab for glucocorticoid-refractory disease, joint monitoring clinically and on imaging, aiming for treat-to-target (low disease activity or remission).^[8][9]
• Still's complicated by MAS (secondary HLH) — a medical emergency at any point; treat with high-dose glucocorticoids and IL-1 inhibitors (see MAS is the resuscitation problem), monitor ferritin, fibrinogen and counts daily, and involve haematology and critical care.^[5]
• Hepatic phenotype — patients presenting with marked transaminitis or acute liver failure need aggressive disease control (steroids, IL-1 blockade) and a hepatology or liver-unit referral; Still's is a recognised cause of acute liver failure requiring transplant assessment.

When Still's kills — the preventable-harm list

Mortality in Still's is concentrated in three scenarios — MAS, fulminant hepatic failure, and cardiac involvement — so vigilance for those three dominates follow-up. Every one of them is treatable if caught; the harm is in the missing.^[2][6]

• Macrophage activation syndrome or secondary HLH — the leading cause of death (complicates about 10 to 15 percent of cases); cytopenias, coagulopathy (low fibrinogen, high PT), liver failure, multi-organ failure. The earliest signature — falling platelets and white cells, falling fibrinogen, rising ferritin, LDH, triglycerides and transaminases with a persistent fever — must trigger treatment, not further investigation.^[2][6]
• Chronic erosive arthritis — in the chronic articular pattern, joint destruction, deformity and disability resembling rheumatoid arthritis (but RF-negative); wrists and small hand joints bear the brunt.
• Secondary (AA) amyloidosis — a long-term consequence of uncontrolled chronic inflammation, presenting as nephrotic-range proteinuria and progressive renal impairment; now rare with effective IL-1 or IL-6 blockade.
• Cardiopulmonary disease — pericarditis and pleuritis are common and usually benign; myocarditis, cardiac tamponade, interstitial pneumonitis and ARDS are rare but lethal.
• Liver disease — transaminitis is common; acute liver failure and hepatic rupture are rare but recognised.
• Treatment-related toxicity — glucocorticoid toxicity (diabetes, osteoporosis, hypertension, infection), NSAID gastropathy and renal effects, methotrexate hepatotoxicity and pneumonitis, and biologic-related infection (reactivation of TB, hepatitis B).
• Diagnostic pitfalls — over-calling Still's before excluding lymphoma or endocarditis (the two most dangerous errors); missing MAS behind a "fever of the underlying disease"; and treating chronic articular Still's as rheumatoid arthritis with hydroxychloroquine and sulfasalazine, which are generally inadequate.

The single most useful prognostic signal is the clinical pattern, established over the first year. Patients who go a full year without relapse are likely to stay in long-term remission; those who develop a persistent polyarthritis within months of onset are the group at risk of chronic joint damage and need early DMARD and IL-6 blockade. A ferritin and CRP that stay elevated despite treatment predict relapse and should prompt intensification, not reassurance.^[2][6]

Prognosis and disposition

Overall prognosis is favourable with modern therapy, but it is pattern-dependent — so name the pattern before you prognosticate.^[1][2]

• The monocyclic pattern remits completely in about 60 to 70 percent of patients within a year and rarely recurs.
• The polycyclic pattern flares but rarely damages joints; long-term morbidity is mainly cumulative steroid toxicity, so steroid-sparing strategies matter.
• The chronic articular pattern carries the greatest long-term morbidity from joint destruction, analogous to seronegative rheumatoid arthritis; early DMARD and IL-6 blockade limits the damage.
• Mortality is about 1 to 5 percent overall, driven by MAS, cardiac involvement and liver failure.
• Disposition: newly diagnosed or flaring Still's is usually admitted for diagnostic workup and initiation of treatment; discharge once fever has settled, markers are falling, and an oral regimen is tolerated. Any suspicion of MAS mandates ICU or HDU admission. Long-term follow-up is under a rheumatologist with monitoring of inflammatory markers, ferritin, FBC and LFTs, and active MAS screening at every flare.^[1]

Special populations

• Children and adolescents: the paediatric counterpart is systemic juvenile idiopathic arthritis (sJIA) — the 2024 EULAR/PReS recommendations designate sJIA and AOSD one disease, to be called Still's disease — and IL-1 inhibitors (anakinra, canakinumab) have proven high efficacy with an excellent safety profile.^[5][9]
• Pregnancy, older age and the immunocompromised: dedicated trial data are scarce; plan with obstetric-medicine, geriatric and transplant input as appropriate, and keep the threshold high for excluding malignancy and infection before attributing the picture to Still's.^[1]

Evidence, guidelines and regional differences

^[1]

Landmark evidence and recent advances:^[6][7][8][9]

• The 2024 EULAR/ACR/PRINTO/PReS recommendations unify the management of Still's disease across the age spectrum (sJIA and AOSD), with IL-1 inhibitors as first-line biologics for systemic disease and IL-6 blockade for chronic articular disease, and explicit guidance on MAS recognition and treatment.^[5]
• Systematic reviews and meta-analyses confirm that canakinumab is effective and reasonably safe in Still's, with high rates of fever clearance and steroid-sparing.^[7]
• Tocilizumab multicentre retrospective data show durable control of refractory disease, particularly for the chronic articular pattern.^[8]
• Therapies targeting the IL-18 and IFN-γ axis and JAK inhibition are emerging for refractory systemic disease and MAS — interferon-γ antagonism has evidence specifically in MAS, and JAK inhibition shows early-administration benefit.^[5][6]

Key facts and mnemonics

^{[1] [1] [2] [3] [13] [1]}

Ward-round test — four stems, thirty seconds each

Stem 1 — the classic trap (answer)ShowHide

A 24-year-old with evening spiking fevers, a salmon-pink rash at the fever peak, a sore throat, a very high ferritin, and negative ANA and RF. The registrar wants to call it Still's and start steroids. What must you do first? Model: Exclude first — Still's is generally reached by exclusion while investigating a fever of unknown origin, and an exclusion process is explicitly required for the Yamaguchi criteria. Infection and malignancy are the classic traps. Only then apply Yamaguchi — five or more criteria including at least two major — and treat. The original criteria set was built on exactly this rule and yielded 96.2 percent sensitivity and 92.1 percent specificity only with the exclusion step applied.^[1][3]

Stem 2 — MAS behind the fever (answer)ShowHide

A known Still's patient on day 5 of a flare: the ferritin has jumped sharply, platelets are falling, fibrinogen is falling, the fever has stopped dipping. What happened, and what do you do in the next hour? Model: This is macrophage activation syndrome (secondary HLH) — the divergence (a ferritin that climbs while fibrinogen and platelets fall) is the signal, and cytopenias, hypertriglyceridaemia and/or hypofibrinogenaemia, and hyperferritinaemia are all HLH-2004 diagnostic criteria. Screen with HLH-2004 (five of eight criteria) or the H-score — haemophagocytosis is only one criterion of eight, so marrow evidence is not a prerequisite. Treat empirically and immediately: per the 2024 EULAR/PReS recommendations, high-dose glucocorticoids and IL-1 inhibitors, with ciclosporin and interferon-γ inhibitors for refractory disease, alongside supportive care for cytopenias and coagulopathy. This is the preventable death in Still's.^[5][10][11]

Stem 3 — which biologic, and why (answer)ShowHide

A patient with the chronic articular pattern — erosive polyarthritis of the wrists and small hand joints — is refractory to glucocorticoids and a conventional DMARD. Which biologic, and why not anakinra? Model: Tocilizumab (anti-IL-6 receptor), 8 mg/kg intravenously every two weeks — effective in glucocorticoid-refractory adult Still's disease in a randomised placebo-controlled phase III trial, with significant improvement in systemic feature scores and a greater glucocorticoid-sparing effect. IL-1 inhibitors (anakinra, canakinumab) are the established option for refractory systemic disease and MAS, and the 2024 EULAR/PReS recommendations favour early use of an IL-1 or IL-6 inhibitor alongside short-duration glucocorticoids.^[5][8]

Stem 4 — state the Yamaguchi major criteria (answer)ShowHide

Name the four Yamaguchi major criteria and the rule for applying them. Model: Four majors — fever over 39 °C for at least one week, arthralgia for at least two weeks, the typical non-pruritic salmon-pink rash, and a neutrophilic leucocytosis over 10 ×10⁹/L with neutrophils over 80 percent. Diagnosis needs five criteria with at least two major, and no exclusion (infection, malignancy, other rheumatic disease). The exclusion clause is the half the candidates forget.^[3]

References13ShowHide

1. [1]Efthimiou P, Kontzias A, Hur P. Adult-onset Still's disease in focus: Clinical manifestations, diagnosis, treatment, and unmet needs in the era of targeted therapies Semin Arthritis Rheum, 2021.PMID 34175791
2. [2]Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult onset Still's disease J Autoimmun, 2018.PMID 30077425
3. [3]Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease J Rheumatol, 1992.PMID 1578458
4. [4]Fautrel B, Zing E, Golmard JL, et al. Proposal for a new set of classification criteria for adult-onset still disease Medicine (Baltimore), 2002.PMID 11997716
5. [5]Fautrel B, Mitrovic S, De Matteis A, et al. EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease Ann Rheum Dis, 2024.PMID 39317417
6. [6]Ruscitti P, Cantarini L, Nigrovic PA, et al. Recent advances and evolving concepts in Still's disease Nat Rev Rheumatol, 2024.PMID 38212542
7. [7]Cota-Arce JM, Cota J, De León-Nava MA, et al. Efficacy and safety of canakinumab in the treatment of adult-onset Still's disease: A systematic review Semin Arthritis Rheum, 2021.PMID 34493394
8. [8]Kaneko Y, Kameda H, Ikeda K, et al. Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment: a randomised, double-blind, placebo-controlled phase III trial Ann Rheum Dis, 2018.PMID 30279267
9. [9]Bindoli S, Baggio C, Doria A, et al. Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options Drugs, 2024.PMID 38441807
10. [10]Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer, 2007.PMID 16937360
11. [11]Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome Arthritis Rheumatol, 2014.PMID 24782338
12. [12]Lebrun D, Mestrallet S, Dehoux M, et al. Validation of the Fautrel classification criteria for adult-onset Still's disease Semin Arthritis Rheum, 2018.PMID 28760536
13. [13]Fautrel B, Le Moël G, Saint-Marcoux B, et al. Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease J Rheumatol, 2001.PMID 11246670