What is the treatment approach for macrophage activation syndrome?

Treatment of Macrophage Activation Syndrome

Initiate high-dose intravenous methylprednisolone (15-30 mg/kg/day, maximum 1g/infusion) immediately upon diagnosis, and add cyclosporine A within 24-48 hours if there is inadequate response or if the patient presents with severe disease. 1

First-Line Treatment: High-Dose Glucocorticoids

High-dose glucocorticoids remain the cornerstone of MAS treatment despite the absence of formal randomized trials—in practice, 97.7% of MAS patients receive glucocorticoids. 2 The evidence supporting this approach comes from extensive clinical experience and international registry data rather than controlled trials, which are not feasible given the rarity and severity of the condition. 2

Dosing regimen:

• Methylprednisolone: 15-30 mg/kg/day IV (maximum 1g/infusion) for 3-5 consecutive days 1, 3
• Dexamethasone: Use instead of methylprednisolone when CNS involvement is present, as it crosses the blood-brain barrier more effectively 1

Second-Line Treatment: Cyclosporine A

Do not wait for treatment failure—add cyclosporine A early (within 24-48 hours) for severe cases or inadequate initial response. 1 Cyclosporine A is the second most frequently used drug after glucocorticoids in clinical practice, though formal trial data is limited to one low-level study. 2

Key evidence for cyclosporine:

• Patients treated with cyclosporine A achieved rapid and complete recovery, with fever resolution within 36 hours of treatment initiation 4
• One patient who did not receive cyclosporine died from rapidly progressive respiratory failure, highlighting the importance of early escalation 4
• Dosing: 2-7 mg/kg/day, administered orally or intravenously (particularly in ICU settings) 1, 5

Biologic Therapies for Refractory or Severe Cases

Anakinra (IL-1 Blockade)

Anakinra shows promising efficacy with complete response rates of 50-100% in published studies, though dosing regimens and administration routes vary. 2 This is particularly effective in Still's disease-related MAS. 1

• Dosing: 2-10 mg/kg/day subcutaneously in divided doses 1, 5
• Often used as second-line treatment but can be considered earlier in severe presentations 2

Emapalumab (Anti-IFN-γ Antibody)

Emapalumab is the only biologic with controlled trial data in MAS, showing >90% complete response rates in patients who failed high-dose glucocorticoids. 2 This represents the highest quality evidence for any MAS treatment beyond glucocorticoids.

• The controlled trial demonstrated marked reduction in glucocorticoid dose alongside high response rates 2
• Reserved for patients with inadequate response to standard therapy 2, 1

Tocilizumab (IL-6 Blockade)

Tocilizumab has increasing evidence for efficacy, particularly in MAS associated with systemic rheumatic conditions and CAR T-cell therapy. 1, 3

JAK Inhibitors

JAK inhibitors (ruxolitinib, baricitinib) show efficacy in case reports of chronic-relapsing MAS not responsive to other therapies. 2, 1 The rationale is strong: MAS demonstrates high expression of genes associated with type I IFN and IFN-γ signaling, with elevated activated T cells producing high IFN-γ levels. 2

Critical Care Management

Transfer to ICU immediately if any of the following are present: 1, 3

• Grade 3 or higher neurotoxicity
• Shock or severe organ dysfunction
• Platelet count <30 g/L
• Grade ≥2 CRS with concurrent neurotoxicity 2

Reassess clinical status at least every 12 hours to determine need for escalation of therapy. 1, 3

Supportive care includes: 3

• Mechanical ventilation as needed
• Vasopressor support
• Renal replacement therapy
• Transfusion support
• Antifungal prophylaxis (strongly consider in patients receiving prolonged steroids) 2, 3

Treatment Algorithm by Clinical Severity

Mild-Moderate MAS

1. High-dose IV methylprednisolone (15-30 mg/kg/day, max 1g) 1
2. Monitor response every 12 hours 1
3. Add cyclosporine A if inadequate response within 24-48 hours 1

Severe MAS or Rapid Deterioration

1. Combination therapy from the start: High-dose methylprednisolone PLUS cyclosporine A 1
2. Consider adding anakinra early 1
3. ICU admission 1, 3
4. If still refractory, escalate to emapalumab 2, 1

MAS with CNS Involvement

1. Dexamethasone instead of methylprednisolone 1
2. Consider lumbar puncture if grade 3-4 neurotoxicity present (after excluding elevated intracranial pressure) 2, 3
3. Repeat neuroimaging every 2-3 days if persistent grade ≥3 neurotoxicity 2

Context-Specific Considerations

Still's Disease-Related MAS

High-dose glucocorticoids, cyclosporine A, anakinra, or tocilizumab are all appropriate options. 1 The evidence for IL-1 and IL-6 blockade is strongest in this population. 2

Malignancy-Associated MAS

Treat both the MAS and the underlying malignancy simultaneously. 1 Consider etoposide as a last resort for refractory cases, though it carries significant toxicity. 3

Infection-Triggered MAS

Initiate appropriate antimicrobial therapy alongside immunosuppressive treatment—do not delay antimicrobials. 1, 3 This is a critical pitfall that increases mortality. 5

CAR T-Cell Therapy-Induced MAS

Tocilizumab is particularly effective in this setting. 3 Note that most moderate-to-severe CRS cases have laboratory abnormalities meeting HLH criteria, but resolve with CRS management alone without requiring specific MAS treatment. 2

MAS Complicating MIS-C

Deviate from standard MIS-C protocols—follow MAS-specific recommendations instead of standard IVIG/glucocorticoid protocols for MIS-C. 1

Monitoring Response to Therapy

Indicators of treatment response: 5

• Decreasing ferritin levels
• Improving cytopenias
• Resolving coagulopathy
• Defervescence

Continue monitoring: 1

• Inflammatory markers (ferritin, CRP, IL-6)
• Complete blood counts
• Coagulation parameters
• Organ function tests
• Reassess at least every 12 hours 1, 3

Critical Pitfalls to Avoid

1. Delayed diagnosis and treatment significantly increases mortality—maintain high suspicion in patients with persistent fever, cytopenias, and ferritin >5000 ng/mL. 5, 3

2. Do not wait for all HLH-2004 criteria to be met before initiating empirical treatment. 3 Early intervention is crucial to prevent irreversible organ damage. 1

3. Do not use glucocorticoids alone in severe cases—high-dose glucocorticoids cannot control hyperinflammation in a significant proportion of patients. 2 Add cyclosporine A early. 1

4. Do not neglect the underlying trigger—simultaneously treat infections, malignancies, or underlying autoimmune disease. 3

5. Do not delay ICU transfer in patients with grade ≥2 organ dysfunction. 3

6. Inadequate antimicrobial therapy when infection is the trigger is a common and deadly mistake. 5

7. For tocilizumab in concurrent CRS and neurotoxicity: Use corticosteroids alone if CRS is grade 1 (fever only) with higher-grade neurotoxicity, as tocilizumab may exacerbate neurotoxicity. 2