What is the treatment for Hemophagocytic Lymphohistiocytosis (HLH) - Macrophage Activation Syndrome (MAS) associated with adult-onset Still's disease?

Treatment of Hemophagocytic Lymphohistiocytosis (HLH) - Macrophage Activation Syndrome (MAS) Associated with Adult-onset Still's Disease

High-dose glucocorticoids are the first-line treatment for HLH-MAS associated with adult-onset Still's disease, with early addition of cyclosporine A and/or anakinra for insufficient response. 1

Initial Treatment Approach

First-Line Therapy

• High-dose glucocorticoids:
  • Intravenous pulse methylprednisolone 15-30 mg/kg/day (maximum 1g/day) for 3-5 consecutive days 1
  • Consider dexamethasone if central nervous system involvement is present (better blood-brain barrier penetration) 1

Second-Line Therapy (for insufficient response to glucocorticoids)

• Calcineurin inhibitors:

  • Cyclosporine A: 2-7 mg/kg/day (oral or IV in critical care settings) 1
  • Alternative: Tacrolimus 1

• IL-1 blockade:

  • Anakinra: 2-10 mg/kg/day in divided doses (higher than standard dose) 1
  • Consider IV administration for severe cases 1

Management of Refractory Cases

For Severe or Rapidly Worsening MAS

• Combination therapy with multiple agents on a background of high-dose glucocorticoids should be considered as initial therapy 1
• Consultation with experts at a reference center is strongly recommended 1

Additional Treatment Options for Refractory Cases

• Anti-IFN-γ antibody:

  • Emapalumab: Shown efficacy in clinical trials for Still's disease-related MAS 1
  • Associated with MAS remission and glucocorticoid-sparing effect 1

• JAK inhibitors:

  • Ruxolitinib or baricitinib: Emerging evidence from case reports 1

• Etoposide:

  • Low-dose etoposide may be considered for refractory cases 1, 2
  • Short-term, low-dose regimen (100 mg twice weekly for 2 weeks) has shown 88% favorable response with acceptable safety profile 2

• Anti-IL-6 therapy:

  • Tocilizumab: Increasing experience in MAS-HLH 1, 3
  • May be particularly effective after failure of etoposide-containing regimens 3
  • Caution: Some reports suggest potential risk of triggering MAS in highly active disease 4

Monitoring and Follow-up

• Frequent reassessment: At least every 12 hours in critically ill patients 1
• Laboratory monitoring: Ferritin, complete blood count, liver function tests, coagulation parameters, triglycerides
• Screen for complications: Secondary infections, organ dysfunction
• Watch for triggers: Infections are common triggers for MAS in Still's disease 1

Important Considerations and Pitfalls

• Early recognition is critical for improved outcomes - MAS occurs in 15-20% of patients with Still's disease 1
• MAS can occur at any point during the disease course, even when Still's disease appears well-controlled on biologic therapy 1
• Higher mortality is reported in adults compared to children with MAS, warranting aggressive treatment 1
• Caution with TNF inhibitors: Etanercept has been associated with worsening of MAS in some cases 5
• Differentiate from sepsis: HLH, multi-organ dysfunction syndrome, and sepsis can coexist, with sepsis potentially triggering HLH 1

Treatment Algorithm

1. Initial assessment: Confirm diagnosis using HLH-2004 criteria or MAS criteria
2. First-line: High-dose pulse methylprednisolone
3. If inadequate response within 24-48 hours: Add cyclosporine A and/or anakinra
4. For severe/refractory cases: Consider combination therapy with emapalumab, JAK inhibitors, or low-dose etoposide
5. For cases failing above therapies: Consider tocilizumab, especially after etoposide failure

This approach balances rapid control of the potentially fatal hyperinflammatory state while addressing the underlying Still's disease pathology.