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 to about 39.5 °C around 7pm, settling back to 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 at 6800 μg/L, ANA and RF negative, neutrophils 17 ×10⁹/L.[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 often over 1000 μg/L (sometimes over 10,000), a neutrophilic leucocytosis (often over 15 ×10⁹/L with neutrophils over 80 percent), raised CRP and ESR, a reactive thrombocytosis, anaemia of chronic disease, ANA and RF negative, glycosylated ferritin under 20 percent, and abnormal LFTs (raised AST/ALT, occasionally cholestatic, rarely acute liver failure).[2]

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 — drives the fever, rash and systemic inflammation, and is why anakinra can defervesce a patient within hours. First-line biologic for systemic disease and for MAS.[7]
• IL-6 — drives the chronic synovitis and the acute-phase response (CRP, ESR, hepatic ferritin synthesis, reactive thrombocytosis). This is why tocilizumab owns the chronic articular pattern.[8]
• IL-18 — released by macrophages and Kupffer cells, the cytokine most tightly linked to MAS. A serum IL-18 over 10,000 pg/mL flags the at-risk patient; anti-IL-18 therapy (tadekinig alfa) is emerging.[6]
• IFN-γ — amplifies the macrophage loop alongside IL-18 and produces the uncontrolled haemophagocytosis of MAS; JAK inhibitors (ruxolitinib) are deployed in refractory MAS for exactly this reason.[9]
• TNF-α — a smaller player than in rheumatoid arthritis; TNF inhibitors (etanercept, adalimumab) are third-line, reserved for selected chronic articular disease.

[1]

Consultant confession: when a Still's patient defervesces within a day of the first anakinra dose, that is not a placebo effect — it is IL-1β being switched off at source. The speed of the response is itself diagnostic reassurance that you have matched the drug to the cytokine.[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 methotrexate and the one in which IL-6 blockade (tocilizumab) earns its place.[1]

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]

[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: overall around 1 to 5 percent, driven mainly by macrophage activation syndrome, liver failure and systemic thrombosis; MAS complicates about 10 to 15 percent of cases and is the leading cause of death.[2][6]

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 — typically over 1000 μg/L, often over 5000, with a glycosylated fraction under 20 percent and the clinical tetrad.
• MAS or secondary HLH — ferritin often over 10,000 μg/L, with falling counts and fibrinogen; this can complicate Still's itself.
• Septic shock or severe bacterial infection — ferritin can be very high, but the clinical picture and positive cultures distinguish it, and the glycosylated fraction usually stays above 20 percent.
• 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 (often over 1000 U/L) dominate.
• Hereditary haemochromatosis or iron overload — chronically high ferritin with a high transferrin saturation (over 45 percent), not an acute febrile illness.
• Chronic alcohol misuse, metabolic dysfunction–associated steatotic liver disease, or unrelated chronic inflammation — moderate elevation, no quotidian fever.[1]

The practical rule: a ferritin over 1000 μg/L with a quotidian fever, a salmon-pink rash, arthritis, negative ANA/RF, and no infection or malignancy is Still's until proven otherwise — but the exclusions are mandatory, not optional.[1]

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: neutrophilic leucocytosis (over 15 ×10⁹/L, neutrophils over 80 percent), reactive thrombocytosis, anaemia of chronic disease. In MAS the counts fall — a dropping neutrophil or platelet count in a febrile Still's patient is a red flag.
• Ferritin: markedly raised — over 1000 μg/L in the great majority, frequently over 5000 and sometimes over 10,000 μg/L. A normal ferritin essentially excludes active Still's.
• Glycosylated ferritin: a fraction under 20 percent is supportive (specificity over 90 percent; sensitivity around 70 to 80 percent); normally 50 to 80 percent is glycosylated.
• CRP and ESR: both markedly raised (CRP often over 100 mg/L); they track disease activity and monitor response.
• Liver function tests: raised AST and ALT (often two to five times the upper limit), sometimes cholestatic; acute liver failure is rare but recognised.
• ANA and RF (and anti-CCP): negative — a cardinal diagnostic feature. If positive, reconsider the diagnosis.
• LDH: raised, and a marker of MAS when it climbs steeply.[1]

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, adapted): HLH/MAS needs either a molecular diagnosis or five of eight criteria — fever, splenomegaly, cytopenias (at least two lineages), hypertriglyceridaemia (over 3 mmol/L) and/or hypofibrinogenaemia (under 1.5 g/L), haemophagocytosis on marrow/spleen/lymph node, low or absent NK-cell activity, ferritin over 500 μg/L (in Still's-MAS often over 10,000), and elevated soluble CD25 (soluble IL-2 receptor alpha). Haemophagocytosis on marrow is supportive but not required — it is frequently absent early.[2][6]

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 folds ferritin and glycosylated ferritin in as major items, and the diagnosis needs four major criteria, or three major plus two minor.[1]

Major criteria (6): fever over 39 °C, arthralgia/arthritis, transient erythema, pharyngitis, neutrophil polymorphonuclear count over 80 percent, and glycosylated ferritin fraction under 20 percent.[1]

Minor criteria (2): maculopapular rash, and ferritin over 1000 μg/L.[1]

MAS is the resuscitation problem

[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, LDH and transaminases), treat it as an emergency: urgent admission, usually ICU or HDU; high-dose IV methylprednisolone pulses (e.g. methylprednisolone 500 mg to 1 g IV once daily for one to three days) then oral prednisolone 1 mg/kg/day, plus anakinra (IL-1 receptor blockade, 100 mg subcutaneously daily); identify and treat any trigger; and support cytopenias, coagulopathy, hepatic and multi-organ failure. Refractory MAS may need ciclosporin, IV immunoglobulin, ruxolitinib, or etoposide-based HLH-2004 protocols under haematology guidance.[9]
• 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 (Fardet 2014) is a weighted score (0 to 337) that captures the degree of abnormality — fever, organomegaly, number of cytopenic lineages, ferritin, AST, triglycerides, fibrinogen, age, immunosuppression, and haemophagocytosis on marrow — with a score over 169 best identifying MAS. In practice the H-score is the more sensitive bedside tool because it weights the trend: a climbing ferritin and a falling fibrinogen count even when the absolute values are still "normal".[2]

Treatment of MAS is empirical and immediate — do not wait for a marrow result. The backbone is IV methylprednisolone pulses (500 mg to 1 g daily for up to three days) followed by oral prednisolone 1 mg/kg/day, plus anakinra 100 mg subcutaneously daily; ciclosporin (3 to 5 mg/kg/day) or IV immunoglobulin (2 g/kg over two to five days) are added for refractory disease, and ruxolitinib or etoposide-based HLH-2004 therapy is reserved for the most refractory cases under haematology guidance. Supportive care — cytopenia support, coagulation correction, trigger treatment, organ support — runs in parallel.[9]

Everyone forgets: haemophagocytosis on the marrow smear is supportive but not required to treat MAS — it is frequently absent early, and waiting for it costs lives. Treat on the trend.[6]

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: naproxen 500 mg orally twice daily (preferred), or ibuprofen 400 to 800 mg orally three times daily, or indometacin 25 to 50 mg orally two to three times daily, with gastric protection. Add a glucocorticoid for systemic features that fail NSAIDs or are moderate at the outset — oral prednisolone 0.5 to 1 mg/kg once daily (typically 30 to 60 mg), tapering slowly once fever and markers normalise (usually over weeks to months). For severe or organ-threatening disease, give IV methylprednisolone pulses (e.g. methylprednisolone 500 mg to 1 g IV daily for one to three days) before stepping down to oral prednisolone.[1]

Step 2 — Chronic articular pattern or steroid-sparing. Introduce a conventional synthetic DMARD, almost always methotrexate 10 to 25 mg orally once weekly with folic acid 5 mg once weekly (on a different day), as the first steroid-sparing agent for the chronic articular pattern or when steroids cannot be tapered. Leflunomide 10 to 20 mg orally once daily is an alternative. Hydroxychloroquine has a limited role and is generally inadequate alone.[2]

Step 3 — Refractory systemic disease (the first-line biologic is an IL-1 inhibitor). For systemic disease that fails glucocorticoids and DMARDs, the 2024 EULAR/ACR recommendations and current evidence put IL-1 blockade first:[5][7]

• Anakinra (recombinant IL-1 receptor antagonist) — 100 mg subcutaneously once daily — the first-line biologic for systemic disease and for MAS, with a rapid (often 24 to 72 hour) defervescence. Weight-based dosing (2 mg/kg/day, max 100 mg) in selected cases.
• Canakinumab (anti-IL-1β monoclonal antibody) — 150 mg subcutaneously every eight weeks (300 mg every four weeks for patients over 100 kg) — a longer dosing interval, useful for maintenance and for responders who want fewer injections.[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 four weeks (or 162 mg subcutaneously every one to two weeks) — the preferred biologic for the chronic articular pattern, with good efficacy on both joint and systemic disease.[8]

Step 5 — Less common or refractory options. TNF inhibitors — etanercept 50 mg subcutaneously weekly, adalimumab 40 mg subcutaneously every two weeks — are less effective for systemic disease but may help selected chronic articular cases. JAK inhibitors (tofacitinib, ruxolitinib) and anti-IL-18 therapy (tadekinig alfa) are emerging for refractory systemic disease and MAS. IV immunoglobulin (2 g/kg over two to five days) and ciclosporin (3 to 5 mg/kg/day) are used in refractory MAS.[6][9]

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 methotrexate and the IL-6 inhibitor tocilizumab, with joint monitoring clinically and on imaging, aiming for treat-to-target (low disease activity or remission).[8]
• Still's complicated by MAS (secondary HLH) — a medical emergency at any point; treat with high-dose IV methylprednisolone plus anakinra (see MAS is the resuscitation problem), monitor ferritin, LDH, fibrinogen and counts daily, and involve haematology and critical care.
• 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

• Pregnancy: plan conception during remission with multidisciplinary care. Glucocorticoids are the safest agent (prednisolone at the lowest effective dose); avoid NSAIDs after 20 weeks gestation (oligohydramnios, premature ductus arteriosus closure); methotrexate is teratogenic and must be stopped at least three months before conception (in men too); leflunomide needs a cholestyramine washout. Anakinra and tocilizumab have limited safety data — avoid where possible and counsel individually, though the benefit in life-threatening MAS may outweigh the risk.[1]
• Children and adolescents: the paediatric counterpart is systemic juvenile idiopathic arthritis (sJIA) — clinically and biologically the same disease; the management principles and the MAS risk are identical, and anakinra and canakinumab are first-line biologics.[5]
• The elderly patient presenting as a fever of unknown origin: a higher threshold for diagnosis — exclude malignancy and endocarditis more aggressively, and lower the threshold for lymph-node and bone-marrow biopsy. Start prednisolone at 0.5 mg/kg (not 1 mg/kg) and watch for steroid toxicity, infection and fluid balance.
• The immunocompromised or post-transplant patient: Still's is rare here, and the differential (lymphoma, infection, drug reaction, haemophagocytic syndrome) must be pursued harder before attributing the picture to Still's.

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]
• IL-18 blockade (tadekinig alfa) and JAK inhibitors (ruxolitinib, tofacitinib) are emerging therapies for refractory systemic disease and MAS, reflecting the central role of the IL-18 and IFN-γ axis.[9]

Key facts and mnemonics

[1] [1] [1]

Ward-round test — four stems, thirty seconds each

Stem 1 — the classic trap (answer)

A 24-year-old with evening spiking fevers to 39.5 °C, a salmon-pink rash at the fever peak, a sore throat, a ferritin of 6800 μg/L, 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 a diagnosis of exclusion, and the exclusions are part of the Yamaguchi criteria, not an afterthought. The two non-negotiable exclusions are lymphoma (LDH, CT chest/abdomen/pelvis, lymph-node or marrow biopsy if nodes or cytopenias) and infective endocarditis (multiple blood cultures, echocardiography). Only then apply Yamaguchi — five criteria, at least two major, no exclusion — and treat. Cultures are taken before steroids; broad-spectrum antibiotics are given if there is any diagnostic doubt and de-escalated once infection is ruled out.[1][3]

Stem 2 — MAS behind the fever (answer)

A known Still's patient on day 5 of a flare: ferritin has jumped from 6000 to 18,000 μg/L, 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 IL-18/IFN-γ axis has run away, and the divergence (a ferritin that climbs while fibrinogen and platelets fall) is the signal. Screen with HLH-2004 (five of eight) or the H-score (over 169) — but do not wait for the marrow, which is often negative early. Treat empirically and immediately: ICU or HDU admission, IV methylprednisolone 500 mg to 1 g daily for one to three days, then oral prednisolone 1 mg/kg/day, plus anakinra 100 mg subcutaneously daily, with supportive care for cytopenias and coagulopathy. This is the preventable death in Still's.[2][6]

Stem 3 — which biologic, and why (answer)

A patient with the chronic articular pattern — erosive polyarthritis of the wrists and small hand joints — is refractory to prednisolone and methotrexate. Which biologic, and why not anakinra? Model: Tocilizumab (anti-IL-6 receptor), 8 mg/kg IV every four weeks. The chronic articular pattern is driven by IL-6 (the synovitis and the acute-phase response), so IL-6 blockade is the match. Anakinra is the right answer for systemic refractory disease and MAS, where IL-1β is the driver. The rule of thumb: IL-1 for systemic, IL-6 for articular; MAS is the emergency.[5][8]

Stem 4 — state the Yamaguchi major criteria (answer)

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]

References

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