What are the alternative therapeutic medications to emapalumab (Interleukin-18 binding protein) for adult and pediatric patients with Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in known or suspected Still’s disease, including Systemic Juvenile Idiopathic Arthritis (sJIA), with inadequate response or intolerance to glucocorticoids, or with recurrent MAS?

Therapeutic Alternatives to Emapalumab for HLH/MAS in Still's Disease

For adult and pediatric patients with HLH/MAS in Still's disease who have inadequate response or intolerance to glucocorticoids, or recurrent MAS, the most effective therapeutic alternatives to emapalumab include high-dose anakinra (IL-1 inhibitor), tocilizumab (IL-6 inhibitor), cyclosporine, and JAK inhibitors such as ruxolitinib or baricitinib. 1

First-Line Alternatives

IL-1 Inhibitors

• Anakinra:
  • Dosing: Higher than standard doses (2-10 mg/kg/day), potentially administered intravenously in repeated doses for severe cases
  • Evidence: Extensive real-world experience with satisfactory responses in numerous patients with MAS 1, 2
  • Particularly valuable in both pediatric and adult patients with Still's disease-related MAS

Calcineurin Inhibitors

• Cyclosporine A:
  • Dosing: 2-7 mg/kg/day (oral or intravenous in critical care settings)
  • Indication: Should be considered in cases of inadequate response to high-dose glucocorticoids 1
  • Particularly valuable in less resourced countries
  • Note: While proven ineffective in primary familial HLH, there is large positive experience with cyclosporine in secondary HLH/MAS 1

IL-6 Inhibitors

• Tocilizumab:
  • Evidence: Has shown efficacy in refractory cases, particularly after failure of etoposide-containing regimens 3
  • Dosing: For SJIA, IV dosing is 8-12 mg/kg for patients <30 kg or 8 mg/kg for patients ≥30 kg every 2 weeks 4
  • Can lead to remission and enable tapering of glucocorticoids 3

Second-Line Alternatives

JAK Inhibitors

• Ruxolitinib/Baricitinib:
  • Emerging therapies with reported efficacy in case reports of refractory MAS 1, 2
  • Mechanism: Target the JAK1/JAK2 pathway which is involved in cytokine signaling

Other Options for Refractory Cases

• Low-dose etoposide:

  • Should be considered in refractory MAS cases 1
  • Used based on successful results in primarily HLH-2004 protocol
  • Caution: Significant toxicity profile requires careful monitoring

• Intravenous Immunoglobulin (IVIG):

  • Dosing: 1-2 g/kg
  • Particularly useful in viral-triggered HLH/MAS 2, 5
  • Used in approximately 67.7% of SJIA-MAS episodes in some cohorts 5

Combination Therapy Approach

The EULAR/PReS task force highlights that combination therapies with multiple agents on a background of high-dose glucocorticoids are often necessary and should be considered as initial therapy, especially in:

• Patients with severe MAS
• Cases with rapid worsening
• Adult patients (who have higher reported mortality) 1

Treatment Algorithm

1. Initial Assessment:

   • Evaluate severity of MAS (fever, ferritin levels, cytopenias, coagulopathy)
   • Screen for infections, particularly viral triggers

2. First-Line Treatment:

   • High-dose glucocorticoids: IV methylprednisolone 15-30 mg/kg/day (max 1g/day) for 3-5 days 1, 2
   • If CNS involvement: Consider dexamethasone (better crosses blood-brain barrier) 1

3. If inadequate response within 24-48 hours, add:

   • Anakinra at high doses (2-10 mg/kg/day) 1, 2 OR
   • Cyclosporine A (2-7 mg/kg/day) 1, 2

4. For severe or rapidly worsening cases:

   • Consider combination therapy from the start
   • Add tocilizumab, particularly if IL-1 inhibition fails 3

5. For refractory cases:

   • Consider JAK inhibitors (ruxolitinib, baricitinib) 1, 2
   • Consider low-dose etoposide with careful monitoring 1
   • Consider plasmapheresis in severe cases 5

Important Considerations

• Early intervention is critical: Mortality increases with delayed treatment - one study showed median duration between symptom onset and hospital admission was significantly longer among patients who died (16.5 vs. 7 days) 5

• Monitoring: Frequent assessment (at least every 12 hours in critically ill patients) of clinical status and laboratory parameters is essential 2

• Infection surveillance: Regular screening for secondary infections or viral reactivations is recommended 2

• Expert consultation: Treatment decisions should be discussed with experts at a reference center, particularly for refractory cases 1

• Age considerations: Higher mortality of MAS is reported in adults compared to children, which may influence treatment aggressiveness 1

• Screening: HLA typing should be performed in patients with Still's disease to assess risk factors for complications 1

The 2024 EULAR/PReS guidelines and systematic review indicate that IL-1 and IL-6 inhibitors show the most favorable risk-benefit ratio compared to alternatives in Still's disease, while high-dose glucocorticoids combined with IL-1 or IFN-γ inhibition currently represent the best available strategy for MAS 1.