What are the treatment recommendations for Macrophage Activation Syndrome (MAS) related to Still's disease?

Treatment of Macrophage Activation Syndrome (MAS) in Still's Disease

High-dose intravenous glucocorticoids (methylprednisolone 15-30 mg/kg/day, maximum 1 g/infusion) are the immediate first-line treatment for MAS, and additional immunosuppressive agents—particularly anakinra at high doses, ciclosporin, or emapalumab—should be added early in patients with inadequate response or severe disease, with combination therapy often necessary from the outset. 1

Immediate First-Line Treatment

High-Dose Glucocorticoids

• Administer intravenous methylprednisolone pulses at 15-30 mg/kg/day (maximum 1 g per infusion) as the cornerstone of initial MAS therapy 1
• Switch to dexamethasone if central nervous system involvement is present, as it crosses the blood-brain barrier more effectively than methylprednisolone 1
• Early initiation of high-dose glucocorticoids achieves satisfactory results in a substantial number of patients, particularly when started promptly 1

Second-Line and Combination Therapies

When to Add Additional Agents

Add second-line agents in two clinical scenarios: 1

• Patients with initial unsatisfactory response to high-dose glucocorticoids
• Patients with severe MAS and rapid clinical worsening

Anakinra (IL-1 Inhibitor)

• Use anakinra at doses substantially higher than standard dosing: >4 mg/kg/day in children or 100 mg twice daily in adults 1
• Administer via repeated intravenous doses rather than standard subcutaneous dosing for severe MAS 1
• Anakinra is the preferred IL-1 inhibitor choice for patients with impending MAS 1
• Real-world experience demonstrates satisfactory responses in multiple patients, though formal clinical trial data in MAS are lacking 1
• High-dose anakinra (up to 48 mg/kg/day intravenously) has been tested in severe sepsis without safety concerns 1
• A case series demonstrated that high-dose anakinra can induce remission even after failure of standard-dose anakinra, cyclosporine, IVIG, etoposide, and tocilizumab 2

Ciclosporin (Calcineurin Inhibitor)

• Consider ciclosporin for inadequate response to glucocorticoids, despite its proven ineffectiveness in primary familial HLH 1
• Large positive real-world experience supports its use in secondary MAS/HLH 1
• Particularly valuable in resource-limited settings 1
• Can be administered orally or intravenously, especially in critical care settings 1
• Combination therapy with glucocorticoids, anakinra, and cyclosporine as a triple regimen may improve clinical outcomes 3

Emapalumab (Anti-IFN-γ Antibody)

• Emapalumab is the only targeted therapy tested in a clinical trial (open-label single arm) specifically for Still's disease-related MAS 1
• In patients with severe MAS who failed high-dose glucocorticoids, emapalumab achieved MAS remission in the great majority of patients with marked glucocorticoid-sparing effect and reassuring safety profile 1
• Important limitation: emapalumab is not yet approved in Europe 1
• A controlled trial in 14 patients showed 93% complete response rate when emapalumab was added to glucocorticoids, cyclosporine, anakinra, and IVIG 1

Third-Line and Refractory Disease Options

JAK Inhibitors

• Consider ruxolitinib or baricitinib (JAK1/JAK2 inhibitors) for refractory MAS based on case report evidence 1
• A case report demonstrated miraculous response to ruxolitinib after failure of corticosteroids, anakinra, tocilizumab, cyclosporine A, and etoposide 4

Etoposide

• Low-dose etoposide may be considered in refractory MAS 1
• Multiple case series show response rates of 56-100% when etoposide is combined with glucocorticoids, cyclosporine, and IVIG 1
• However, one case report showed inadequate response to etoposide but remarkable response to additional tocilizumab 5

Tocilizumab (IL-6 Inhibitor)

• Tocilizumab has mixed evidence in MAS treatment 6, 5, 7
• In SJIA clinical trials, MAS occurred in 3% of patients during open-label tocilizumab treatment, with a rate of 2.8/100 patient-years 6
• One case report showed successful short-term tocilizumab for refractory MAS after etoposide failure 5
• Caution: one case report documented MAS manifestation after tocilizumab initiation in highly active AOSD, though tocilizumab was useful for maintenance therapy after MAS resolution 7

Critical Treatment Principles

Combination Therapy Approach

Combination therapies with multiple agents on a background of high-dose glucocorticoids are often necessary and should be considered as initial therapy in severe cases 1

Mortality Considerations

• Higher mortality in adults with MAS should influence treatment selection and combination therapy decisions 1
• All treatment decisions for severe or refractory MAS should be discussed with experts at reference centers 1

Diagnostic Screening Criteria

When to Suspect MAS

Consider MAS in Still's disease patients presenting with: 1

• Persistent fever
• Splenomegaly
• Elevated or rising serum ferritin
• Inappropriately low cell counts (cytopenias)
• Abnormal liver function tests
• Intravascular activation of coagulation
• Elevated or rising serum triglycerides

Timing of MAS Development

MAS can develop at any point during Still's disease course: 1

• At disease onset
• During initial diagnostic workup
• During biologic DMARD treatment even when Still's disease is well controlled
• During drug tapering

Common Pitfalls

• Avoid using standard-dose anakinra (1-2 mg/kg/day) in MAS—substantially higher doses are required for efficacy 1
• Do not delay addition of second-line agents in patients with severe MAS or inadequate glucocorticoid response 1
• Do not assume tocilizumab is contraindicated in MAS—while it may trigger MAS in highly active disease, it has shown efficacy in some refractory cases 5, 7
• Remember that ciclosporin, while ineffective in primary HLH, has substantial positive experience in secondary MAS 1