Recommended Initial Treatment for Macrophage Activation Syndrome
High-dose intravenous glucocorticoids (methylprednisolone 10-30 mg/kg/day or equivalent) should be initiated immediately as first-line therapy for macrophage activation syndrome, with early consideration for combination therapy with ciclosporin, anakinra, or emapalumab in severe cases or those with inadequate initial response. 1
First-Line Treatment Approach
Immediate Initiation of High-Dose Glucocorticoids
The cornerstone of MAS treatment is high-dose intravenous glucocorticoids, particularly methylprednisolone (3-30 mg/kg/day, maximum 1 g/infusion) or prednisone (0.4-3 mg/kg/day). 2, 1 Dexamethasone should be specifically chosen when central nervous system involvement is present due to superior blood-brain barrier penetration. 1
High-dose glucocorticoids can achieve satisfactory results in a substantial number of patients, particularly when initiated early. 1 The 2024 EULAR/PRES guidelines emphasize that early treatment is critical for mortality reduction.
Second-Line and Combination Therapies
When to Escalate Beyond Glucocorticoids Alone
Combination therapies with multiple agents on a background of high-dose glucocorticoids are often necessary and should be considered as initial therapy in severe MAS with rapid worsening. 1 The decision to add additional agents should be made early rather than waiting for treatment failure.
Ciclosporin (Cyclosporin A)
Ciclosporin should be considered with inadequate response to glucocorticoids alone. 1 It can be administered intravenously or orally at doses of 2-8 mg/kg/day. 2 In the systematic review, 6 of 9 evaluable patients achieved complete response with ciclosporin, and it demonstrated glucocorticoid-sparing effects in all cases. 2 This agent is particularly valuable in resource-limited settings. 1
Important caveat: While ciclosporin has proven ineffective in primary familial HLH and has been dropped from that protocol, the extensive positive real-world experience in secondary MAS supports its continued use in this context. 1
Anakinra (IL-1 Inhibitor)
Anakinra demonstrated a 73% complete response rate (32/44 patients) in Still's disease-associated MAS. 2 Critical dosing consideration: Anakinra must be used at doses higher than the standard 1-2 mg/kg/day, preferably with intravenous repeated dosing for optimal efficacy in MAS. 1 The systematic review found favorable outcomes in 83% of sJIA-MAS patients treated with anakinra. 3
Emapalumab (Anti-IFN-γ Antibody)
Emapalumab is the only targeted therapy tested in a clinical trial for Still's disease-related MAS, showing 93% achievement of complete MAS remission (13/14 patients) in those who had failed high-dose glucocorticoids. 2, 1 The regimen used was 6 mg/kg initially, followed by 3 mg/kg every 3 days until day 15, then twice weekly until day 28, always combined with high-dose methylprednisolone. 2
Emapalumab demonstrated marked glucocorticoid-sparing effects and a reassuring safety profile, with adverse events mainly limited to viral infections (one CMV reactivation as serious adverse event). 2, 1 Important limitation: Emapalumab is not yet approved in Europe. 1
Recent evidence suggests low-dose emapalumab may be effective in refractory cases, with 88.9% achieving complete remission and median prednisone dose reduction of 85.5%. 4
Refractory MAS Treatment
Etoposide
Low-dose etoposide may be considered in refractory MAS. 1 In the systematic review, all 5 evaluable patients achieved complete response with etoposide (always combined with glucocorticoids), though one case of neutropenic sepsis was reported. 2 Etoposide is mainly used as part of the HLH-94/04 protocol. 3
JAK Inhibitors
Ruxolitinib and baricitinib (JAK1/JAK2 inhibitors) have shown efficacy in case reports of refractory MAS. 1, 5 However, evidence remains limited to case reports and cannot yet be recommended as standard therapy.
Treatment Algorithm
- Immediate: High-dose IV methylprednisolone (10-30 mg/kg/day)
- Severe presentation or inadequate initial response within 24-48 hours: Add ciclosporin (2-8 mg/kg/day) OR high-dose anakinra (>2 mg/kg/day IV)
- Failed standard therapy: Consider emapalumab (if available) at 6 mg/kg initial dose
- Refractory disease: Low-dose etoposide or JAK inhibitors in consultation with reference center
Critical Clinical Considerations
Higher Mortality in Adults
The higher mortality of MAS in adults compared to children should influence the threshold for initiating combination therapy early. 1 Do not delay escalation in adult patients.
Expert Consultation
Decisions regarding combination therapy should be discussed with experts at a reference center, particularly for severe or refractory cases. 1
Infectious Triggers
Pursue appropriate studies to identify potential infectious triggers, as management should be directed toward treating triggering infections alongside immunosuppression. 6 This is particularly important in rheumatic disease patients where viral triggers are common.
Monitoring for Complications
Watch for CMV reactivation, particularly with emapalumab and intensive immunosuppression. 2, 4 Neutropenic sepsis risk exists with etoposide. 2