What is the treatment for macrophage activation syndrome?

Treatment of Macrophage Activation Syndrome

High-dose intravenous glucocorticoids are the immediate first-line treatment for macrophage activation syndrome, with methylprednisolone 15-30 mg/kg/day (maximum 1g/infusion) administered as pulse therapy, and cyclosporine A should be added within 24-48 hours for severe cases or inadequate initial response. 1

Initial Treatment Approach

First-Line Therapy

• Initiate high-dose pulse methylprednisolone immediately upon diagnosis at 1g/day intravenously for 3-5 consecutive days in adults, or 15-30 mg/kg/day (maximum 1g/infusion) in pediatric patients 1
• Switch to dexamethasone when central nervous system involvement is present, as it crosses the blood-brain barrier more effectively than methylprednisolone 1
• Early treatment initiation is critical to prevent irreversible organ damage and improve survival 1

When to Add Cyclosporine A

• Add cyclosporine A for severe cases or inadequate response within 24-48 hours of glucocorticoid initiation 1
• Dose cyclosporine at 2-7 mg/kg/day, administered orally or intravenously, particularly in critical care settings 1, 2
• Cyclosporine is effective despite the absence of formal clinical trials, based on extensive clinical experience 1

Alternative First-Line Agents

• Anakinra (IL-1 receptor antagonist) at 2-10 mg/kg/day subcutaneously in divided doses is an effective alternative or addition to cyclosporine, particularly in Still's disease-related MAS 1, 3
• Anakinra can be used as part of combination therapy on a background of high-dose glucocorticoids 1

Second-Line and Refractory MAS

For Inadequate Response to Initial Therapy

• Tocilizumab (IL-6 blockade) has increasing evidence for efficacy in MAS, particularly when associated with systemic rheumatic conditions 1
• Case reports demonstrate successful use of tocilizumab for refractory MAS after failure of glucocorticoids, cyclosporine, and even etoposide 4, 5

Advanced Therapies for Severe Refractory Cases

• Emapalumab (anti-IFN-γ antibody) has shown efficacy in clinical trials for Still's disease-related MAS, achieving remission in the majority of patients who failed standard care with high-dose glucocorticoids 1
• Emapalumab has been successfully used in combination with etoposide, anakinra, tacrolimus, and corticosteroids for infection-induced MAS 6
• JAK inhibitors (ruxolitinib or baricitinib) have shown efficacy in case reports of refractory MAS 1
• Etoposide may be considered in severe cases, though it carries significant immunosuppressive risks 3, 2

Treatment by MAS Subtype

Still's Disease-Related MAS

• Use high-dose glucocorticoids, cyclosporine A, anakinra, or tocilizumab as recommended first-line options 1
• Combination therapies with multiple agents are often necessary and should be considered as initial therapy in severe presentations 1

Infection-Triggered MAS

• Initiate appropriate antimicrobial therapy alongside immunosuppressive treatment 1
• The case of adenoviremia-triggered MAS required combination therapy with emapalumab, etoposide, anakinra, tacrolimus, and corticosteroids 6

Malignancy-Associated MAS

• Treatment must target both the MAS and the underlying malignancy 1
• Etoposide-containing regimens are particularly effective for malignancy-associated cases 2

Critical Care Management

Monitoring Requirements

• Reassess clinical status at least every 12 hours to determine need for escalation of therapy 1, 2
• Consider ICU admission for patients with shock, severe organ dysfunction, or grade 3 or higher neurotoxicity 1
• Serial laboratory testing should monitor ferritin levels, complete blood count, coagulation parameters, and liver function tests 3

Supportive Care

• Provide ventilation, vasopressors, renal replacement therapy, and transfusions as needed 2
• Manage coagulopathy, cardiac dysfunction, and multi-organ failure aggressively 3

Common Pitfalls to Avoid

• Delayed diagnosis and treatment significantly increases mortality - do not wait for all diagnostic criteria to be met before initiating therapy 2
• MAS is frequently underdiagnosed because features overlap with severe cytokine release syndrome, sepsis, or disease flares 3
• Inadequate use of antimicrobials when infection is the primary trigger can lead to treatment failure 2
• Biologics given after insufficient immunosuppressive therapy may paradoxically cause or worsen MAS 5
• The absence of hemophagocytosis on bone marrow examination does not exclude MAS - serial assessment may be necessary 3

Special Considerations

• For neonatal MAS in infants born to mothers with autoimmune disease, treatment with steroids, intravenous immunoglobulin, and cyclosporine has been successful 7
• Plasmapheresis combined with tacrolimus may be effective for steroid-refractory MAS, particularly in dermatomyositis patients 8
• Note that MIS-C treatment recommendations differ from MAS - patients with MIS-C who develop overt MAS require deviation from standard MIS-C protocols 9