Adult-Onset Still Disease

• IL-18 and IL-1β Hyperproduction: The hallmark pathophysiologic feature involves excessive production of interleukin-18 (IL-18) and interleukin-1β (IL-1β) by activated macrophages and dendritic cells, often 10-100 fold higher than in other inflammatory conditions. These cytokines drive systemic inflammation through activation of the NLRP3 inflammasome, a multiprotein complex that processes pro-IL-1β and pro-IL-18 into their active forms. The elevated IL-18 is the most specific biomarker for AOSD, with levels correlating with disease activity, fever spikes, and systemic manifestations. This explains the dramatic response to IL-1 inhibitors in many patients and the failure of TNF-α inhibitors in some cases, distinguishing AOSD from conventional autoimmune arthropathies.

• Altered Th17 Cell Differentiation and Neutrophil Recruitment: Dysregulated T-cell differentiation favors expansion of Th17 cells, which produce IL-17, driving neutrophil recruitment to tissues. IL-18 from macrophages synergizes with IL-12 to promote interferon-γ (IFN-γ) production, creating a pro-inflammatory microenvironment. This neutrophil-predominant infiltrate explains the high peripheral blood neutrophilic leukocytosis (often >15,000/μL) and contributes to the pathologic tissue damage in joints and other organs. The activation of neutrophils generates reactive oxygen species and releases proteolytic enzymes, perpetuating inflammation.

• Defective Regulatory T Cell (Treg) Function and Impaired IL-10 Production: Patients with AOSD demonstrate reduced numbers and function of CD4+CD25+Foxp3+ regulatory T cells, with decreased production of the immunosuppressive cytokine IL-10. This defect in immune tolerance allows unchecked expansion of pro-inflammatory effector T cells. Additionally, there is impaired production of TGF-β, another critical anti-inflammatory cytokine. The loss of this counter-regulatory mechanism explains the persistent systemic inflammation and the difficulty in controlling disease with conventional immunosuppression alone in some patients.

• Genetic Susceptibility and Environmental Triggers: Although no clear HLA associations have been established (unlike most autoimmune conditions), familial clustering and monozygotic twin concordance suggest genetic predisposition. Suspected environmental triggers include viral infections (particularly parvovirus B19, EBV, and hepatitis C in some cases), though causation remains unproven. Genetic variants in genes encoding components of the inflammasome pathway, iron metabolism genes (ferritin), and toll-like receptor signaling have been implicated in susceptibility.

• Hyperferritinemia as a Secondary Manifestation: The marked elevation of serum ferritin (often >10 times upper limit of normal) is a consequence rather than a cause of disease, resulting from hepatic synthesis stimulated by IL-6 and other inflammatory cytokines. Ferritin itself acts as a danger-associated molecular pattern (DAMP), further amplifying inflammation through pattern recognition receptors. The hyperferritinemia correlates better with systemic inflammation (fever, hepatosplenomegaly) than with articular disease, making it a useful biomarker of visceral involvement.

• Presumed Viral Triggers: Molecular mimicry between viral antigens and self-antigens has been proposed for several pathogens including parvovirus B19, EBV, CMV, and hepatitis C virus, though definitive causation remains unproven. The temporal relationship between viral infection and disease onset in some patients supports a triggering role, though most infected individuals never develop AOSD. The hypothesis suggests that initial viral infection activates the innate immune system, which in genetically predisposed individuals fails to resolve appropriately.

• Genetic Predisposition Without Major HLA Association: Unlike most autoimmune rheumatologic diseases, AOSD lacks strong HLA associations, supporting its autoinflammatory rather than autoimmune pathogenesis. Genome-wide association studies have identified variants in genes related to inflammasome components and IL-1 signaling. Familial AOSD cases are rare but documented, suggesting genetic factors that remain largely uncharacterized. The variable penetrance and expressivity suggest complex polygenic inheritance with environmental modifiers.

• Aberrant Drug Reactions: Rarely, medications including certain antibiotics (penicillins, sulfonamides), hydantoins, and other agents have been temporally associated with AOSD-like presentations. The mechanisms are unknown but may involve aberrant T-cell activation or direct inflammasome stimulation. These drug-induced cases may have different treatment responses and prognoses compared to idiopathic AOSD.

• Possible Dysregulated Response to Iron Overload: Elevated body iron stores (though not primary hemochromatosis) have been noted in AOSD, and iron can promote inflammasome activation and Th17 differentiation. However, whether this is a primary causative factor or secondary consequence remains unclear, and iron overload is not necessary or sufficient for AOSD development.

Cardinal Symptoms

• High Spiking Fevers (Quotidian Pattern): The fever is the hallmark feature, characteristically occurring once daily in late afternoon or evening (quotidian pattern), often spiking to ≥39°C (≥102.2°F), with rapid defervescence to normal by morning. The fever is accompanied by constitutional symptoms (malaise, chills, fatigue) and may be the only symptom some days, leading to diagnostic confusion if missed. The fever typically does not respond to antibiotics (distinguishing from infection) but responds dramatically to NSAIDs or corticosteroids. Some patients report that fever peaks coincide with the appearance or worsening of rash and arthralgia.

• Evanescent (Salmon-Colored) Rash: An intensely pruritic, salmon or coral-colored urticarial rash appears typically during fever spikes and resolves completely as fever abates, often within hours. The rash is non-blanching or only partially blanching and typically appears on the trunk and proximal extremities but can generalize. The rash lacks the scale or crusting of secondary infection, distinguishing it from infected urticaria. The evanescent nature combined with fever can lead to misdiagnosis as recurrent infection or allergy if the temporal relationship is not recognized.

• Arthralgia and Arthritis: Most patients experience symmetrical polyarthralgia involving knees, wrists, ankles, and shoulders; approximately 80-90% develop frank arthritis during the disease course. The arthritis resembles early RA with morning stiffness (often 1-2 hours) and swelling, though rheumatoid factor and anti-CCP antibodies are negative. The arthritis can be seronegative rheumatoid-like or, less commonly, resolved or minimal in some patients. Notably, chronic destructive arthropathy with erosions and joint damage develops in 8-15% of patients, particularly those with persistent polyarticular involvement, resembling seronegative RA.

Systemic Manifestations

• Hepatosplenomegaly and Lymphadenopathy: Present in 50-90% of patients, liver and spleen enlargement can be substantial and correlates with systemic inflammation and hyperferritinemia. Generalized lymphadenopathy (particularly cervical and axillary nodes) is common and may be mistaken for lymphoma; biopsy shows reactive hyperplasia. Liver function abnormalities with elevated transaminases occur in 50-75% of patients, though severe hepatic dysfunction is uncommon; cholestasis is rare unless macrophage activation syndrome develops.

• Serositis and Cardiac Manifestations: Pleuritis occurs in 5-15% of patients, presenting with pleuritic chest pain and pleural effusions (typically exudative with elevated LDH and normal glucose). Pericarditis develops in 2-6% of cases, occasionally with significant pericardial effusion; overt tamponade is rare. Myocarditis is less common but can contribute to cardiac dysfunction. These cardiac manifestations typically respond to NSAIDs or corticosteroids but must be distinguished from infectious and malignant causes.

• Pulmonary Involvement: Interstitial lung disease (ILD) develops in 1-5% of cases, with NSIP (non-specific interstitial pneumonia) pattern being most common histologically; UIP pattern is less frequent. Acute respiratory distress syndrome (ARDS) can develop as part of macrophage activation syndrome (MAS). Cryptogenic organizing pneumonia has been reported. Progressive ILD is an important cause of morbidity and mortality in AOSD, requiring early detection and aggressive treatment.

• Renal Involvement: Glomerulonephritis is uncommon (1-3% of cases) but when present typically manifests as IgA nephropathy or lupus-like glomerulonephritis with positive ANA. Secondary amyloidosis (AA amyloidosis) can develop from chronic inflammation in longstanding untreated disease, presenting with proteinuria and progressive renal failure. These renal manifestations may not be clinically apparent until advanced, necessitating regular urinalysis screening.

Physical Examination Findings

• Salmon-colored Rash Distribution: The rash is most prominent on the trunk, proximal extremities, and neck but characteristically appears and disappears with fever spikes. The rash blanches partially or incompletely with pressure, and patients often cannot demonstrate it to the clinician because it resolves so quickly. Documentation with photography during fever spikes aids diagnosis.

• Joint Examination: Symmetric swelling and warmth of wrists, knees, ankles, and proximal interphalangeal joints; morning stiffness lasting 1-2 hours; absence of rheumatoid nodules (unlike RA). The arthritis pattern may mimic early RA or psoriatic arthritis, but negative serologies and the systemic features differentiate AOSD.

Important Clinical Variants

• Monocyclic Pattern: 30-40% of patients experience a single disease episode lasting weeks to months followed by complete remission; approximately 10-20% have permanent remission after the initial episode. These patients have excellent prognosis with minimal joint damage.

• Polycyclic/Intermittent Pattern: 40-50% of patients have recurrent flares separated by disease-free intervals; predictability of flares is variable. These patients may develop chronic arthritis between flares.

• Chronic Pattern: 10-20% develop persistent active disease with continuous symptoms and progressive joint damage. These patients carry the highest morbidity and require long-term immunosuppression, resembling seronegative RA.

• Macrophage Activation Syndrome (MAS): A life-threatening complication occurring in 8-15% of AOSD patients, characterized by hemophagocytosis and uncontrolled macrophage activation. Presents with high fever unresponsive to NSAIDs, progressive pancytopenia, hepatosplenomegaly, coagulopathy, elevated ferritin (often >10,000), elevated LDH, and elevated triglycerides. Associated with high mortality (10-25%) if not recognized and treated emergently.

Diagnostic Criteria (Yamaguchi Criteria - Most Widely Used)

• Daily quotidian fever ≥39°C (≥102.2°F)
• Evanescent salmon-colored rash
• Arthralgia or arthritis
• Leukocytosis ≥11,000/μL (including >80% neutrophils)

• Hepatomegaly or splenomegaly
• Lymphadenopathy
• Liver dysfunction (transaminitis)
• Negative ANA and negative RF (supports diagnosis)

Laboratory Studies

• Complete Blood Count with Differential: Marked neutrophilic leukocytosis (WBC 10,000-50,000/μL with >80% neutrophils) present in >95% of patients during fever; normal counts do not exclude AOSD. Thrombocytosis (platelets >400,000/μL) occurs in 40-50% and correlates with disease activity. Anemia of chronic disease develops in prolonged disease; thrombocytopenia is a warning sign for MAS.

• Inflammatory Markers - ESR and CRP: Elevated ESR and CRP reflecting acute phase response; CRP often dramatically elevated (>50 mg/dL). ESR/CRP levels correlate with systemic inflammation and fever spikes but not necessarily with arthritis severity, distinguishing from RA where markers correlate with articular disease.

• Hyperferritinemia (Most Specific Finding): Serum ferritin >10 times upper limit of normal is highly suggestive of AOSD when combined with clinical features; levels often 5,000-30,000 ng/mL (normal <200 ng/mL in females, <300 ng/mL in males). Ferritin elevation correlates better with systemic manifestations (fever, hepatosplenomegaly, MAS risk) than with arthritis severity. Glycosylated ferritin (ferritin with reduced carbohydrate side chains) is decreased in AOSD and may be more specific than total ferritin; a ratio of glycosylated to total ferritin <0.26 has high specificity but is not widely available.

• Liver Function Tests: Elevated transaminases (AST and ALT) 1.5-5× upper limit of normal in 50-75% of patients; cholestasis is atypical and should prompt consideration of alternative diagnoses. Liver dysfunction typically improves with disease control. Severe hepatic dysfunction should raise concern for MAS or alternative diagnoses.

• Negative Autoimmune Serology: Rheumatoid factor and anti-CCP antibodies negative in >95% of patients (critical for distinguishing from RA). Antinuclear antibodies (ANA) negative in >95%; positive ANA should prompt consideration of SLE or other connective tissue diseases. Absence of autoantibodies supports the diagnosis of an autoinflammatory rather than autoimmune condition.

• Additional Laboratory Findings: Low albumin reflecting chronic inflammation; elevated LDH in systemic inflammation; elevated D-dimer and prolonged PT/INR warn of MAS; elevated triglycerides and low fibrinogen suggest MAS development. Procalcitonin is typically normal or mildly elevated (unlike bacterial sepsis where very high).

Imaging Studies

• Chest X-ray: May reveal pleural effusions (5-15% of patients) or rarely interstitial patterns consistent with ILD. Serial imaging helps monitor for pulmonary involvement and excludes other diagnoses (malignancy, infection).

• Hand and Wrist Radiographs: Early disease shows soft tissue swelling without osseous changes. Chronic disease (8-15% of cases) may develop erosions and joint space narrowing resembling seronegative RA, particularly in the wrists, PIPs, and MCPs. The delayed development of erosions (typically after >1 year of persistent polyarthritis)

Immediate priorities

• Exclude infection and malignancy before immunosuppression: obtain blood cultures and appropriate imaging; empiric antibiotics are reasonable while sepsis remains on the differential, since AOSD fever is antibiotic-unresponsive but sepsis is lethal if missed.
• Recognize macrophage activation syndrome (MAS): falling cell counts, rising ferritin/triglycerides, and falling fibrinogen mandate ICU-level care and immediate high-dose IV glucocorticoids (pulse methylprednisolone) rather than stepwise outpatient therapy.

First-line therapy

• NSAIDs (e.g., indomethacin, naproxen): adequate only for mild, fever/arthralgia-predominant disease; monotherapy controls a minority and should not delay escalation.
• Systemic glucocorticoids (prednisone, or pulse methylprednisolone for organ-threatening disease): the standard induction agent, producing rapid defervescence. The 2024 EULAR/PReS recommendations for Still disease frame glucocorticoids as bridging therapy, with early transition to a targeted agent to limit steroid toxicity.

Escalation and steroid-sparing therapy

• IL-1 inhibitors (anakinra; canakinumab): mechanistically first-line biologics given IL-1β/IL-18–driven inflammasome activation. EULAR/PReS endorses early IL-1 (or IL-6) blockade — the window of opportunity concept — in systemically active disease.
• IL-6 inhibitor (tocilizumab): alternative targeted agent, favored when arthritis predominates.
• Conventional DMARDs (methotrexate): useful for chronic articular disease and as a steroid-sparing agent; ineffective for acute systemic crisis.
• TNF inhibitors: generally less effective than IL-1/IL-6 blockade in AOSD; reserved for refractory articular disease.
• Refractory MAS: cyclosporine, and etoposide-containing HLH-directed protocols in fulminant cases.

Cautions and contraindications

• Screen before biologics: latent tuberculosis and hepatitis B; live vaccines are contraindicated during biologic or high-dose steroid therapy.
• NSAIDs: avoid with significant transaminitis, coagulopathy, or renal impairment.
• Methotrexate: contraindicated in pregnancy and significant liver disease.
• Tocilizumab: normalizes CRP and blunts fever, so these cannot be used to exclude infection; clinical vigilance is required, and routine safety labs (CBC with differential, transaminases, lipids) must still be monitored on schedule.

Disease-related — emergencies

• Macrophage activation syndrome (secondary HLH) — emergency: unchecked macrophage/CD8 T-cell activation with IFN-γ and IL-18 excess causes hemophagocytosis. Signaled by fever that stops remitting, cytopenias, ferritin often >10,000 ng/mL, hypertriglyceridemia, hypofibrinogenemia, and a paradoxically falling ESR (fibrinogen consumption) despite a high CRP.
• Disseminated intravascular coagulation and fulminant hepatic failure — emergency: cytokine-driven endothelial and hepatocyte injury; signaled by rising INR, falling fibrinogen, encephalopathy, and jaundice (cholestasis is otherwise atypical for AOSD).
• Cardiac tamponade / myocarditis — emergency: serositis with rapid effusion accumulation; pulsus paradoxus, hypotension, electrical alternans.
• ARDS — emergency: acute diffuse alveolar injury during a systemic flare or MAS, with bilateral infiltrates and hypoxemia refractory to supplemental oxygen.

Disease-related — chronic/subacute

• Pulmonary hypertension and pulmonary alveolar proteinosis: a distinct, subacute vascular/alveolar entity described mainly in systemic JIA and less often in AOSD; presents insidiously with exertional dyspnea and a falling DLCO rather than acute alveolar injury. An association with IL-1/IL-6 inhibitor exposure has been debated and is not established as causal.
• Erosive, destructive arthropathy: persistent synovitis, classically fusing the wrist/carpus; radiographic carpal ankylosis after prolonged polyarticular disease.
• AA (secondary) amyloidosis: chronic serum amyloid A elevation from unremitting inflammation; heralded by new proteinuria and rising creatinine — screen with periodic urinalysis.
• Interstitial lung disease: progressive dyspnea with restrictive PFTs and falling DLCO.

Treatment-related

• Glucocorticoids: infection, hyperglycemia, osteoporosis with fragility fracture, and osteonecrosis (new hip pain on weight-bearing with normal early radiographs — MRI is the sensitive test).
• Methotrexate: transaminitis, cytopenias from folate antagonism, and hypersensitivity pneumonitis presenting as subacute dry cough and hypoxemia.
• Biologics (IL-1, IL-6, TNF inhibitors): serious bacterial infection and tuberculosis reactivation — emergency when febrile neutropenia or sepsis develops, particularly because tocilizumab suppresses CRP and fever and can mask an abdominal catastrophe such as diverticular perforation.
• Anakinra: injection-site reactions and neutropenia.

• The stem triad: young adult with quotidian (once-daily, evening) spiking fever ≥39°C, an evanescent salmon-colored rash present only during the spike, arthralgia, and a neutrophil-predominant leukocytosis. If the rash "disappeared by the time the doctor arrived," think AOSD.
• Ferritin is the association examiners test: extreme hyperferritinemia (often >10× the upper limit of normal) with negative RF and negative ANA. A low glycosylated ferritin fraction is the more specific but less available refinement.
• **The rash exhibits *Koebner phenomenon***: scratching or pressure elicits it. Antecedent nonsuppurative sore throat is a classic early feature — a minor criterion in the Yamaguchi criteria and a major criterion in the Fautrel criteria.
• Single best next step is almost never a biologic: it is exclusion — blood cultures, viral serologies, and imaging (± lymph node biopsy) for infection and lymphoma, because AOSD remains a diagnosis of exclusion under the Yamaguchi criteria.
• The MAS trigger to recognize: continuous rather than remittent fever with falling platelets, falling WBC, falling fibrinogen, falling ESR, and rising triglycerides/ferritin. A dropping ESR with a rising CRP in a Still patient is an emergency, not improvement.
• Mechanism drives therapy: IL-1β/IL-18 excess explains why glucocorticoids induce remission and why IL-1 blockade (anakinra, canakinumab) or IL-6 blockade (tocilizumab) is the preferred steroid-sparing step per the 2024 EULAR/PReS Still disease recommendations.
• Common distractors to avoid: seropositive RA (AOSD is RF/anti-CCP negative and has no rheumatoid nodules), SLE (ANA-negative in AOSD), adult lymphoma (fever and adenopathy overlap — nodes show reactive hyperplasia), and hereditary hemochromatosis (high ferritin but normal-to-low CRP and no fever).
• Do not attribute the ferritin elevation to iron overload — it is IL-6-driven acute-phase synthesis; transferrin saturation is not the answer.