What are the treatment guidelines for patients with Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in known or suspected Still’s disease, including Systemic Juvenile Idiopathic Arthritis (sJIA), who have an inadequate response or intolerance to glucocorticoids, or with recurrent MAS?

Treatment Guidelines for HLH/MAS in Still's Disease with Inadequate Response to Glucocorticoids

For patients with HLH/MAS in known or suspected Still's disease (including sJIA) who have inadequate response to glucocorticoids or recurrent MAS, biologic DMARDs (IL-1 and IL-6 inhibitors) are strongly recommended over continued long-term glucocorticoid therapy or calcineurin inhibitors alone. 1

Initial Assessment and Management

Diagnostic Considerations

• Rule out infections as triggers for MAS before or concurrently with initiating therapy 1
• Key laboratory markers: extreme hyperferritinemia, cytopenias, hypofibrinogenemia, hypertriglyceridemia, elevated transaminases, and falling ESR with elevated CRP 2
• Bone marrow biopsy showing hemophagocytosis is supportive but not essential for diagnosis 2

First-Line Therapy for MAS

• High-dose glucocorticoids are conditionally recommended as part of initial treatment 1
  • IV methylprednisolone pulse (30 mg/kg/day, maximum 1 g/infusion)
  • Consider dexamethasone for central nervous system involvement 1
  • Limit to shortest duration possible due to adverse effects on growth and bone health 1

Treatment Algorithm for Glucocorticoid-Inadequate Response

Biologic Therapy Options

1. IL-1 Inhibitors (first choice) 1

   • Anakinra at higher than standard doses (>2 mg/kg/day)
   • Consider IV administration for severe cases
   • Rapid effectiveness documented in refractory MAS 2

2. IL-6 Inhibitors 1

   • Tocilizumab is conditionally recommended
   • No preferred agent between IL-1 and IL-6 inhibitors

Additional Therapies for Refractory Cases

1. Combination Therapy Approach 1

   • Biologic DMARDs + calcineurin inhibitors often necessary in severe cases
   • Consider early combination in patients with rapid clinical deterioration

2. Calcineurin Inhibitors 1

   • Cyclosporine A for inadequate response to glucocorticoids
   • Tacrolimus as an alternative option
   • Particularly valuable in resource-limited settings 1

3. Emerging Therapies (for highly refractory cases) 1, 3

   • Emapalumab (anti-IFN-γ antibody) - showed 93% remission rate by week 8 in a prospective trial
   • JAK inhibitors (ruxolitinib, baricitinib) - case reports of efficacy
   • Low-dose etoposide - consider in extremely refractory cases

4. Other Interventions 4, 5, 6

   • IVIG - reported in 67.7% of sJIA-MAS episodes
   • Plasmapheresis - for severe cases with multi-organ involvement
   • Consider early referral to tertiary centers for refractory cases

Monitoring and Follow-up

Disease Activity Assessment

• Monitor ferritin, CBC, fibrinogen, triglycerides, and liver enzymes frequently
• Declining ferritin and improving cytopenias suggest treatment response
• Screen for lung disease with pulse oximetry and DLCO measurement 1

Treatment Tapering

• Once MAS is controlled, taper glucocorticoids first before attempting to taper biologic DMARDs 1
• Tapering and discontinuing glucocorticoids is strongly recommended after inactive disease is attained 1
• Biologic DMARDs may be tapered more gradually after sustained remission

Special Considerations

Recurrent MAS

• Associated with higher mortality and lung disease development 1
• Consider more aggressive initial combination therapy
• Earlier introduction of biologics is recommended
• Maintenance therapy with IL-1 or IL-6 inhibitors may prevent recurrence

Mortality Risk Factors

• Delayed diagnosis and treatment (>7 days from symptom onset) 4
• Hepatosplenomegaly 4
• Multi-organ involvement
• Need for ICU admission

Pitfalls and Caveats

• Delay in diagnosis significantly increases mortality risk - early recognition is crucial 4, 5
• MAS can be difficult to distinguish from flares of underlying disease or infection
• Viral infections (particularly CMV) should be screened for during treatment with biologics 3
• ESR may paradoxically decrease during MAS despite worsening inflammation
• Combination therapy decisions should involve experts from reference centers 1