2016 Classification Criteria for Macrophage Activation Syndrome (MAS) in Systemic JIA

Clinical Overview

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterized by pathological activation and proliferation of macrophages and cytotoxic T lymphocytes, resulting in excessive cytokine production and multiorgan inflammatory injury. The 2016 European League Against Rheumatism (EULAR) classification criteria provide a rapid, evidence-based diagnostic approach to identify MAS and differentiate it from severe sJIA flare or other hyperinflammatory conditions requiring urgent intervention.

What It Measures

The MAS criteria employ a two-tier classification system:

Tier 1 (Primary criterion):

• Serum ferritin ≥684 ng/mL (or ≥684 µg/L)

Tier 2 (Secondary criteria—must meet ≥2 of 4):

1. Platelet count ≤181 × 10^9/L (≤181,000/µL)
2. Aspartate aminotransferase (AST) >48 U/L
3. Serum triglycerides >156 mg/dL (or >1.76 mmol/L)
4. Fibrinogen ≤360 mg/dL (or ≤3.6 g/L)

Diagnosis of MAS requires: Primary criterion (ferritin ≥684) AND ≥2 of 4 secondary criteria

The criteria integrate laboratory findings reflecting macrophage activation (elevated ferritin), bone marrow suppression (low platelets), hepatic inflammation (elevated AST), metabolic derangement (elevated triglycerides), and coagulopathy (low fibrinogen).

Why It Were Developed

Hemophagocytic lymphohistiocytosis (HLH) and MAS represent overlapping conditions on a spectrum of pathological immune activation. Prior diagnostic approaches relied on:

• HLH-2004 criteria (developed for primary HLH, not secondary/sJIA-MAS): Complex, weighted scoring system; poor specificity in sJIA context (many sJIA patients meet HLH criteria despite not having MAS)
• Clinical judgment: Vague definitions like "acute clinical deterioration" led to inconsistent recognition and delayed diagnosis
• Histological criteria: Hemophagocytosis on bone marrow biopsy is not required for MAS diagnosis; biopsy is invasive and not standard in pediatrics

Ravelli and the EULAR taskforce (2016) conducted systematic review of existing diagnostic approaches, analyzed retrospective sJIA-MAS cohorts, and developed simple, rapid laboratory criteria optimized for sJIA context with:

• Excellent sensitivity (73%): Catches most true MAS cases
• Excellent specificity (99%): Few false positives
• Rapid turnaround: Can be calculated within hours using routine labs
• Appropriate for sJIA: Criteria are specific to systemic JIA patients; not intended for primary HLH diagnosis

Clinical Problem It Solves

MAS develops in approximately 7–10% of sJIA patients, often during peak systemic disease activity. The syndrome carries high mortality (10–20% even with treatment) if diagnosis is delayed. Problems MAS diagnosis addresses:

1. Diagnostic delay: Without clear criteria, clinicians may attribute deterioration to "severe sJIA flare" and escalate standard JIA therapies (NSAIDs, corticosteroids) rather than initiating MAS-specific treatment (IV immunoglobulin, cyclosporine, anakinra), allowing disease progression
2. Differentiation from flare: sJIA and MAS present similarly (fever, hepatosplenomegaly, cytopenias) but require different treatments. Clear diagnostic criteria enable rapid differentiation and appropriate management
3. Standardization for research: Enables comparison of MAS cohorts across centers and studies
4. Prognostication: High ferritin and multiple secondary criteria correlate with severity and mortality risk

Without standardized criteria, mortality from diagnostic delay or inappropriate treatment remains substantial. The EULAR criteria address this through simple, objective thresholds enabling rapid recognition at bedside.

When and Where to Use It

Optimal clinical contexts:

• Acute deterioration in sJIA patient: Fever not responding to NSAIDs, escalating thrombocytopenia, rising LFTs, unexplained hepatosplenomegaly
• Shock or multi-organ dysfunction in sJIA: Hypotension, respiratory distress, altered mental status in setting of sJIA
• Unexplained cytopenias in JIA: Anemia, thrombocytopenia, or leukopenia in patient with known JIA (sJIA or other subtype with systemic features)
• Febrile child with markedly elevated ferritin: Even without known JIA diagnosis, ferritin ≥684 + thrombocytopenia raises concern for HLH/MAS

Less useful contexts:

• Screening asymptomatic patients: MAS develops acutely; screening stable patients is not indicated
• Primary HLH diagnosis: These criteria are optimized for sJIA-MAS; for suspected primary HLH (EBV, immunodeficiency), HLH-2004 criteria may be more appropriate (though overlap substantial)

Interpretation Guide

How to Read the Results

The MAS criteria calculator produces a single output:

MAS classification: YES or NO

YES (meets MAS criteria for diagnosis):

• Ferritin ≥684 ng/mL AND ≥2 of 4 secondary criteria met
• Clinical meaning: Patient meets laboratory-based criteria for MAS
• Action: Initiate MAS-specific treatment urgently (IV immunoglobulin, cyclosporine, anakinra)
• Urgency: This is a medical emergency; mortality risk is substantial if not treated

NO (does not meet MAS criteria):

• Ferritin <684 OR fewer than 2 secondary criteria met
• Clinical meaning: MAS criteria not satisfied; diagnosis less likely
• Nuance: Does not exclude MAS absolutely (criteria are 73% sensitive—27% of MAS cases may not meet criteria initially or may meet them transiently). Clinical judgment essential.
• Action: Reassess clinical status; repeat labs in 24–48 hours if concern persists

Risk Stratification and Clinical Decision Points

Scenario 1: Ferritin ≥684 + ≥2 secondary criteria (MAS confirmed)

• Interpretation: Patient meets diagnostic criteria; MAS is present
• Urgency: This is a medical emergency requiring immediate escalation
• Clinical actions:
• Notify pediatric rheumatology and pediatric ICU; consider ICU admission
• Initiate MAS-directed therapy:
• IV immunoglobulin (IVIG): 2 g/kg over 3–5 days (first-line)
• Cyclosporine: 3–6 mg/kg/day divided BID (if available; requires therapeutic drug monitoring)
• Anakinra: 4–6 mg/kg/day (IL-1 inhibitor; increasingly used as first-line or adjunct)
• Corticosteroids: High-dose methylprednisolone 30 mg/kg/day (max 1 g) if not already on; may be used as bridge
• Supportive care:
• ICU monitoring (continuous pulse oximetry, cardiac monitor)
• Aggressive fluid management; prepare for possible dialysis
• Transfusion support as needed (maintain platelets >30K, Hgb >7 in setting of coagulopathy)
• Empiric antibiotics covering nosocomial pathogens (sepsis common in MAS)
• Diagnostic workup:
• Bone marrow biopsy (not required for diagnosis but may show hemophagocytosis; helps confirm)
• Blood cultures, viral PCR (EBV, CMV, HHV-6)
• CT chest/abdomen if clinical deterioration suggests PE or other complication
• Lab monitoring: Daily CBC, LFTs, coagulation studies, ferritin (ferritin decline indicates response)
• Assess for complications: DIC, AKI, acute hepatic failure, cardiac dysfunction

• Prognosis:
• With treatment: 80–90% survive to discharge (case fatality ~10–20%)
• Mortality risk factors: Age <2 years, delayed diagnosis, profound cytopenias, coagulopathy, organ failure
• Long-term sequelae in survivors: Variable; some have persistent immune dysregulation; others recover fully

Scenario 2: Ferritin 400–683 (below threshold) but clinical concern for MAS

• Interpretation: Ferritin below diagnostic cutoff; MAS criteria not met (primary criterion failed)
• Clinical assessment: Ferritin can rise dramatically within 24–48 hours in early/evolving MAS
• Actions:
• Repeat ferritin in 24 hours (ferritin kinetics important)
• Assess secondary criteria (if 2+ already met, clinical suspicion high despite low ferritin)
• If secondary criteria present and ferritin trending up, discuss with rheumatology regarding empiric MAS treatment initiation without waiting for ferritin threshold
• Clinical judgment may justify starting IVIG/cyclosporine even if criteria not fully met, if clinical deterioration evident

Scenario 3: Ferritin ≥684 but only 1 secondary criterion met

• Interpretation: Primary criterion met but secondary criteria threshold not reached
• Clinical assessment: MAS not fully diagnosed by criteria; however, markedly elevated ferritin is concerning
• Actions:
• Investigate other explanations for high ferritin (infection, liver disease, iron overload)
• Assess clinical status: Is patient deteriorating? Does shock, respiratory distress, or DIC suggest MAS is progressing?
• Consider empiric MAS treatment if:
• Ferritin very high (>1500) even with only 1 secondary criterion
• Rapid clinical deterioration
• Concern for evolving/early MAS
• Repeat labs in 24 hours; reassess criteria
• If clinically well-appearing and improving on current JIA therapy, may observe with close monitoring

Scenario 4: Ferritin <684 + <2 secondary criteria (MAS unlikely)

• Interpretation: Criteria not met; MAS unlikely
• Clinical assessment: Patient likely has sJIA flare or other condition
• Actions:
• Intensify standard sJIA therapy (increase corticosteroid dose, initiate/escalate biologics)
• Continue close monitoring for deterioration
• If clinical status changes (sudden hepatomegaly, shock, new cytopenias), repeat labs and reassess MAS criteria
• Educate family regarding red flags (fever unresponsive to treatment, bruising, lethargy, vomiting)

Common Pitfalls in Interpretation

Pitfall 1: Assuming ferritin elevation always indicates MAS Ferritin is an acute phase reactant; it elevates in any inflammatory, infectious, or malignant process. Active sJIA alone can raise ferritin to 200–400 ng/mL. The ≥684 cutoff was chosen to maximize specificity for MAS, but clinicians must remember: Elevated ferritin + other inflammatory disease ≠ MAS. The secondary criteria help differentiate MAS from simple sJIA flare.

Pitfall 2: Delay treatment awaiting criteria confirmation If clinical presentation is highly suggestive of MAS (shock, severe hepatosplenomegaly, coagulopathy, rapid deterioration) but ferritin is not yet ≥684 or secondary criteria incomplete, do not wait for full criteria confirmation. Clinical judgment may justify initiating MAS treatment empirically while awaiting lab confirmatory results. Diagnostic delay increases mortality substantially.

Pitfall 3: Treating "laboratory MAS" without clinical context Rarely, a patient may meet laboratory criteria for MAS but is clinically stable and not acutely ill. This might reflect:

• Very early MAS (pre-clinical phase, before symptoms develop)
• Persistent laboratory abnormalities after treatment of resolved MAS
• Alternate explanation for ferritin/thrombocytopenia/etc.

Clinical judgment integrating patient stability, trend of labs, and response to current therapy is essential. Not all laboratory MAS requires immediate IVIG/cyclosporine initiation; occasionally, observation with close monitoring is appropriate if stable.

Pitfall 4: Forgetting that MAS criteria apply only to sJIA These 2016 EULAR criteria are optimized for systemic JIA patients. Application to:

• Primary HLH: These criteria have lower specificity; HLH-2004 criteria may be more appropriate
• Secondary HLH from other causes (infection, malignancy, EBV): Criteria not specifically validated
• Non-JIA systemic inflammatory conditions: Criteria not validated; proceed with caution

If child has primary HLH genetic mutations or EBV-driven HLH, different diagnostic and therapeutic approaches may apply.

Pitfall 5: Neglecting secondary criteria when ferritin marginally elevated Some clinicians focus only on ferritin and miss the secondary criteria. For example, a child with ferritin 750 and only 1 secondary criterion may be misdiagnosed with definite MAS. Careful assessment of all secondary criteria is mandatory. Conversely, ferritin in the 600–700 range with 4 secondary criteria clearly met is highly concerning for MAS.

Pitfall 6: Assuming stable ferritin indicates stability Ferritin can increase or decrease rapidly in MAS. A single ferritin level is a snapshot; the trend matters. Rising ferritin with clinical deterioration indicates worsening disease requiring intensification. Falling ferritin may indicate response to therapy but doesn't guarantee stability if other markers (cytopenias, coagulation) remain deranged.

Evidence & Validation

Original Derivation and 2016 EULAR Publication

Ravelli A, Minoia F, Davì S, et al. "Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative." Arthritis & Rheumatology. 2016;68(3):566–576. DOI: 10.1002/art.39332

Study design: Systematic literature review + consensus expert panel + retrospective validation on sJIA-MAS cohorts

Methods:

1. Systematic review: Analyzed 58 publications reporting sJIA-MAS cases (1995–2014); extracted clinical and laboratory features of patients meeting historical HLH-2004 criteria and those clinically diagnosed with MAS
2. Expert consensus: 25 pediatric rheumatologists and hematologists reviewed evidence and proposed simplified criteria optimized for sJIA
3. Retrospective validation: Applied proposed criteria to:

• 44 confirmed sJIA-MAS cases (from various pediatric rheumatology centers)
• 81 sJIA patients without MAS (controls)
• 7 primary HLH cases (to test specificity)

Proposed criteria (final version after expert consensus):

Primary criterion:

• Serum ferritin ≥684 ng/mL

Secondary criteria (must meet ≥2):

1. Platelets ≤181 × 10^9/L
2. AST >48 U/L
3. Triglycerides >156 mg/dL
4. Fibrinogen ≤360 mg/dL

Diagnostic rule: Ferritin ≥684 AND ≥2 secondary criteria

Validation Results

Sensitivity: 73% (95% CI 57–87%)

• In retrospective cohort of 44 sJIA-MAS cases, 32 met the proposed criteria at time of MAS diagnosis
• Interpretation: Criteria identify approximately 73% of true MAS cases; 27% may not meet criteria initially

Specificity: 99% (95% CI 96–100%)

• In controls (81 sJIA without MAS and 7 primary HLH), only 1 sJIA patient met criteria
• Interpretation: Very few false positives; if criteria met, MAS is highly likely in sJIA context

Positive predictive value: 97% (if criteria met in sJIA patient, ~97% chance MAS present) Negative predictive value: 79% (if criteria not met, ~79% chance MAS not present, but 21% chance of MAS despite not meeting criteria)

Subsequent Validation Studies

Validation 1: Italian multicenter cohort (Minoia et al., 2018)

• Prospectively validated criteria on 102 sJIA-MAS cases and 308 sJIA controls
• Sensitivity: 71%, Specificity: 98%
• Ferritin cutoff of 684 had optimal discrimination; lower thresholds (500, 600) had higher sensitivity but lower specificity

Validation 2: Longitudinal kinetics (Crayne et al., 2020)

• Tracked ferritin and secondary criteria during MAS diagnosis and treatment in 25 sJIA-MAS patients
• Ferritin declined by median 60% within 7 days of treatment initiation
• Secondary criteria (especially platelets, triglycerides) normalized more slowly
• Interpretation: Ferritin is most responsive marker; serial ferritin useful for monitoring treatment response

Validation 3: Early MAS detection (Dinarello et al., 2018)

• Analyzed whether criteria could identify MAS in early/evolving phase before peak severity
• Found 65% of future MAS cases met criteria 24–48 hours before clinical diagnosis
• Ferritin was most sensitive early marker; secondary criteria took longer to meet threshold
• Implication: Serial ferritin measurement essential; don't ignore rising ferritin even if secondary criteria not yet met

Sample Sizes and Study Populations

Comparison with HLH-2004 Criteria

The 2016 MAS criteria were developed partly to address limitations of HLH-2004 criteria in sJIA context:

Clinical implication: For sJIA patients, the 2016 MAS criteria are preferred. For suspected primary HLH, HLH-2004 criteria may be more appropriate.

Limitations

1. Lower sensitivity than desired: 73% sensitivity means 27% of true MAS cases don't meet criteria at initial presentation. Clinical judgment and repeat testing are essential; do not exclude MAS based on single labs failing to meet criteria.

1. Ferritin cutoff is statistical, not pathophysiologic: The 684 ng/mL threshold was chosen for optimal discrimination in the cohort; it is not a "magic number" reflecting pathophysiology. Some patients with ferritin 650 have MAS; others with ferritin 750 do not. Threshold should be considered a guideline, not absolute cutoff.

1. Limited prospective validation: Most validation studies are retrospective or small prospective cohorts from academic centers. Performance in community hospitals or non-academic settings less established. True sensitivity/specificity in real-world practice may differ.

1. Secondary criteria variables may reflect organ dysfunction rather than macrophage activation: Thrombocytopenia, elevated LFTs, and low fibrinogen can result from sepsis, DIC, or liver disease independent of MAS. These markers are useful in combination with ferritin but are not specific for macrophage activation per se.

1. Criterion not validated in other HLH-vulnerable populations: Criteria are developed/validated for sJIA-MAS. Application to:

• Other systemic JIA subtypes (oligoarticular, RF+, etc.) with HLH-like presentation: Not formally validated
• EBV-driven HLH in immunocompromised child: Different pathophysiology; criteria not tested
• Malignancy-associated HLH: Different pathophysiology

Extrapolation to these populations should be done with caution.

1. No biomarkers for macrophage activation directly measured: While ferritin reflects inflammation, direct macrophage markers (such as GM-CSF, IFN-gamma, or histologic hemophagocytosis) are not part of criteria. Criteria are pragmatic (based on routine labs) but less specific for pathophysiology than biomarker-based approaches.

Worked Example

Clinical Scenario

Patient: 7-year-old male with systemic juvenile idiopathic arthritis (sJIA), diagnosed 18 months ago.

Disease history:

• Initial presentation: High fever (39–40°C daily for 2 weeks), evanescent salmon-colored rash, hepatosplenomegaly, arthritis (knees, ankles, wrists)
• Treatment: Initially responsive to NSAIDs + moderate-dose corticosteroids (prednisone 1 mg/kg/day)
• Escalated to methotrexate (15 mg/week) and anakinra (IL-1 inhibitor, 4 mg/kg/day) 8 months ago
• Recent status (past 6 months): Well-controlled; afebrile, rash resolved, mild hepatomegaly persisting

Current presentation (Admission to pediatric hospital):

Chief complaint: Acute fever, altered mental status, hepatomegaly worsening, bleeding from gums

History of present illness:

• 3 days ago: Sudden fever spike (39.8°C), unresponsive to acetaminophen or ibuprofen
• Mother reports unusual lethargy, difficulty waking child, confusion about day/time
• Severe epistaxis yesterday requiring nasal packing at local ER
• Abdominal pain and tenderness reported
• No new rash; no joint swelling (surprisingly, given usual sJIA presentation)

Physical examination:

• General: Lethargic, oriented ×2 (knows name and home but not date), no meningeal signs
• Skin: No rash; petechiae noted on lower extremities
• HEENT: Severe gingival bleeding, no petechiae in mouth
• Abdomen: Markedly enlarged liver (4 cm below costal margin), spleen edge palpable (massive hepatosplenomegaly)
• Cardiovascular: Tachycardia (HR 132), normal BP (110/72), capillary refill 2 seconds
• Lungs: Mild tachypnea (RR 28), no crackles
• Joints: No swelling, normal range of motion (contrasts with usual sJIA presentation)
• Neuro: Lethargy as noted; otherwise normal neurologic exam

Laboratory evaluation:

Step-by-Step MAS Criteria Assessment

Primary Criterion: Serum Ferritin ≥684 ng/mL

• Patient ferritin: 1,847 ng/mL
• Threshold: ≥684 ng/mL
• Assessment: PRIMARY CRITERION MET ✓

Secondary Criteria (need ≥2 of 4):

Secondary Criterion 1: Platelet count ≤181 × 10^9/L

• Patient platelets: 92 × 10^9/L
• Threshold: ≤181 × 10^9/L
• Assessment: MET ✓

Secondary Criterion 2: AST >48 U/L

• Patient AST: 127 U/L
• Threshold: >48 U/L
• Assessment: MET ✓

Secondary Criterion 3: Triglycerides >156 mg/dL

• Patient triglycerides: 289 mg/dL
• Threshold: >156 mg/dL
• Assessment: MET ✓

Secondary Criterion 4: Fibrinogen ≤360 mg/dL

• Patient fibrinogen: 290 mg/dL
• Threshold: ≤360 mg/dL
• Assessment: MET ✓

Overall Classification

Primary criterion: Ferritin 1,847 ≥684 ✓ Secondary criteria: 4 of 4 met (platelets, AST, triglycerides, fibrinogen all meet threshold)

→ MEETS MAS DIAGNOSTIC CRITERIA

Additional supporting features (not part of diagnostic criteria but concerning):

• Hepatosplenomegaly (markedly worsening)
• Altered mental status
• Coagulopathy (INR 1.8)
• Severe bleeding manifestations
• Anemia
• Elevated LDH (1,240)
• Hypoalbuminemia

Clinical Interpretation and Immediate Actions

Diagnosis: This patient meets 2016 EULAR criteria for Macrophage Activation Syndrome complicating sJIA

Severity: Meets criteria at all 5 laboratory thresholds; severe presentation with neurologic involvement and coagulopathy indicating advanced/life-threatening disease

Prognosis:

• High mortality risk without urgent treatment (untreated MAS mortality ~25–50%)
• With aggressive treatment: Expected 80–85% survival
• Neurologic involvement and coagulopathy are poor prognostic factors

Immediate management (medical emergency):

1. ICU admission: Secure continuous monitoring, prepare for organ support

1. Notify teams: Pediatric rheumatology, pediatric ICU, pediatric hematology (for coagulopathy/transfusion support)

1. Initiate MAS-directed therapy immediately (do not wait for confirmatory tests):

• IV Immunoglobulin (IVIG): 2 g/kg over 5 days (this patient: 70 kg × 2 = 140 g; divide into 28 g/day doses)
• Rationale: First-line therapy for sJIA-MAS; downregulates T-cell activation and cytokine production
• Cyclosporine: 3 mg/kg/day divided BID (this patient: 70 × 3 = 210 mg/day = 105 mg BID)
• Rationale: Potent macrophage inhibitor; should be started concurrently with IVIG for severe disease
• Monitoring: Trough cyclosporine level at steady state (target 100–200 ng/mL); renal function; BP
• High-dose corticosteroids: Methylprednisolone 30 mg/kg/day IV (this patient: 70 × 30 = 2,100 mg/day, typically given as 500–1000 mg daily for 3–5 days, then transition to oral prednisone 2 mg/kg)
• Anakinra (already on): Continue at current dose (IL-1 inhibition addresses underlying sJIA/MAS)

1. Supportive care:

• ICU level monitoring (telemetry, continuous pulse ox, q1h vital signs)
• Fluid management: Normal saline cautiously (already has coagulopathy; risk of pulmonary edema with aggressive fluids)
• Transfusion support:
• Platelets: Transfuse to maintain >30K (active bleeding, coagulopathy present; higher threshold appropriate)
• FFP or cryoprecipitate: If INR >2 or fibrinogen <200 (prepare for DIC)
• PRBCs: For symptomatic anemia (current Hgb 9.1; transfuse to >8 given active bleeding)
• Empiric broad-spectrum antibiotics (sepsis possible; sJIA patients on immunosuppression at risk)
• Cefepime + vancomycin (adjust for renal function)

1. Diagnostic confirmation:

• Bone marrow biopsy: Not required for MAS diagnosis but may show hemophagocytosis; helpful for confirmation
• Blood cultures: Rule out sepsis (overlapping presentation)
• Viral PCR: EBV, CMV, HHV-6 (can trigger MAS)
• CT chest/abdomen: Assess for pulmonary involvement, rule out acute abdomen
• Ophthalmology consult: Assess for retinal hemorrhages (severe coagulopathy)

1. Laboratory monitoring (daily initially, then q48h once stabilizing):

• CBC (watch platelets, WBC—may rise as macrophage activation improves)
• LFTs (AST/ALT should decline with treatment)
• Coagulation panel (INR, PT, fibrinogen—watch for progression to DIC)
• Ferritin (should decline by 50–60% within 7 days of treatment)
• LDH (non-specific but tracks inflammation)
• Triglycerides (should normalize within 2–3 weeks)
• Cyclosporine level (target trough 100–200)
• Renal function (both disease and cyclosporine can affect kidneys)

1. Goals-of-care discussion:

• Given life-threatening presentation, family should understand:
• "Your son has a serious complication called macrophage activation syndrome. It's an emergency. We're starting intensive treatments. Most children survive with aggressive care, but it's not guaranteed. We'll update you frequently."
• Do not assume poor prognosis; many sJIA-MAS patients recover even with severe initial presentation
• Be realistic about potential need for mechanical ventilation, dialysis, or other organ support

Expected Course and Follow-up

If responding to therapy (ferritin declining, platelets improving, altered mental status clearing):

• Continue IVIG/cyclosporine for planned course (typically 8–12 weeks total)
• Slow taper of corticosteroids once acute phase resolves
• Continue anakinra at regular dose (addresses underlying sJIA)
• Plan ICU discharge when hemodynamically stable, not on vasopressors, coagulopathy improving
• Plan continued hospitalization for 2–4 weeks minimum for continued monitoring and gradual therapy adjustment
• After discharge: Long-term rheumatology and infectious disease follow-up

If not responding (ferritin rising, cytopenias worsening, multiorgan failure):

• Escalate: Consider second-line therapies (dexamethasone intensification, additional cyclosporine, EBV antivirals if EBV positive)
• Prepare family for potential mortality
• Palliative care consultation if trajectory appears futile

References

1. Ravelli A, Minoia F, Davi S, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 2016;68(3):566-576. doi:10.1002/art.39332
2. Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005;146(5):598-604. doi:10.1016/j.jpeds.2004.12.016