What is the treatment 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, 2

First-Line Treatment: High-Dose Glucocorticoids

• High-dose glucocorticoids are the cornerstone of MAS treatment, with 97.7% of MAS patients receiving this therapy despite the absence of formal randomized trials 2
• The American College of Rheumatology recommends methylprednisolone 15-30 mg/kg/day IV (maximum 1g/infusion) for 3-5 consecutive days 1, 2
• When central nervous system involvement is present, switch to dexamethasone as it better crosses the blood-brain barrier 1
• Early initiation is crucial to prevent irreversible organ damage and improve survival 1

Second-Line Treatment: Cyclosporine A

• Add cyclosporine A early (within 24-48 hours) for severe cases or inadequate initial response to glucocorticoids 1, 2
• Dosing is 2-7 mg/kg/day, administered orally or intravenously, particularly in the critical care setting 1, 2
• The European League Against Rheumatism recommends cyclosporine A due to its effectiveness despite the absence of formal clinical trials 1
• Cyclosporine should be added to first-line therapy of MAS, as patients treated with cyclosporine achieved rapid and complete recovery with fever abating within 36 hours 3

Biologic Therapies for Refractory or Severe Cases

Anakinra (IL-1 Receptor Antagonist)

• Anakinra shows complete response rates of 50-100% in published studies, particularly in Still's disease-related MAS 2
• Dosing is 2-10 mg/kg/day subcutaneously in divided doses 1, 2
• Triple therapy with anakinra, systemic glucocorticoids, and cyclosporine may improve clinical outcomes, with all patients in one cohort surviving when this regimen was used early 4

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
• Reserved for patients with inadequate response to standard therapy 2
• Achieved remission in the majority of patients with Still's disease-related MAS who had failed standard care 1

Tocilizumab (IL-6 Blockade)

• Tocilizumab has increasing evidence for efficacy in MAS-HLH, particularly when associated with systemic rheumatic conditions and CAR T-cell therapy 1, 2

JAK Inhibitors

• Ruxolitinib or baricitinib show efficacy in case reports of chronic-relapsing MAS not responsive to other therapies 1, 2
• Strong rationale based on high expression of genes associated with type I IFN and IFN-γ signaling 2

Treatment Algorithm by Clinical Severity

Mild-Moderate MAS

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

Severe MAS or Rapid Deterioration

• Use combination therapy from the start: high-dose methylprednisolone AND cyclosporine A 2
• Consider adding anakinra early 2
• Transfer to ICU immediately 2
• Reassess clinical status at least every 12 hours 1, 2

Context-Specific Treatment Considerations

Still's Disease-Related MAS

• High-dose glucocorticoids, cyclosporine A, anakinra, or tocilizumab are all appropriate options 1, 2
• Strongest evidence exists for IL-1 and IL-6 blockade in this population 2

Malignancy-Associated MAS

• Treat both the MAS and the underlying malignancy simultaneously 1, 2
• Consider etoposide as a last resort for refractory cases, though it carries significant toxicity 2

Infection-Triggered MAS

• Initiate appropriate antimicrobial therapy alongside immunosuppressive treatment without delay 1, 2
• Inadequate antimicrobial therapy is a common and deadly mistake 2

MAS Complicating MIS-C

• Treatment must deviate from standard MIS-C protocols when overt MAS develops 1
• Follow MAS-specific recommendations instead of standard IVIG/glucocorticoid protocols for MIS-C 1

Dengue-Associated MAS

• Treatment should simultaneously address both the MAS and the underlying dengue infection 5

Critical Care Management

ICU Admission Criteria

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

Supportive Care

• Mechanical ventilation as needed 2
• Vasopressor support 2
• Renal replacement therapy 2
• Transfusion support 2
• Antifungal prophylaxis 2

Monitoring Response to Therapy

• Reassess clinical status at least every 12 hours to determine need for escalation of therapy 1, 2
• Monitor decreasing ferritin levels, improving cytopenias, resolving coagulopathy, and defervescence 2, 5
• Sequential monitoring of BNP/NT-proBNP and troponin T levels 1
• EKG at minimum every 48 hours in hospitalized patients to detect conduction abnormalities 1
• Continue monitoring inflammatory markers, complete blood counts, coagulation parameters, and organ function tests at least every 12 hours 2

Critical Pitfalls to Avoid

• Do not wait for all HLH-2004 criteria to be met before initiating empirical treatment, as early intervention is crucial to prevent irreversible organ damage 2
• Do not use glucocorticoids alone in severe cases—add cyclosporine A early, as high-dose glucocorticoids cannot control hyperinflammation in a significant proportion of patients 2
• Delayed diagnosis and treatment significantly increases mortality; maintain high suspicion in patients with persistent fever, cytopenias, and ferritin >5000 ng/mL 2
• In Kawasaki disease, persistent fever greater than 10 days is highly associated with development of MAS, and ferritin levels should be checked if there are unexplained clinical exacerbations 6