What is the treatment approach for Macrophage Activation Syndrome (MAS) in a pediatric patient with Systemic Onset Juvenile Idiopathic Arthritis (SOJIA)?

Treatment of Macrophage Activation Syndrome in Systemic-Onset Juvenile Idiopathic Arthritis

For MAS in SOJIA patients, immediately initiate high-dose intravenous methylprednisolone (15-30 mg/kg/day, maximum 1g/infusion) combined with IL-1 or IL-6 inhibitors, and add cyclosporine A within 24-48 hours if there is inadequate response or severe presentation. 1, 2

Initial Assessment and Urgent Considerations

Before initiating immunosuppressive therapy, all children with MAS must be evaluated for infection concurrently with or prior to treatment initiation, as infections frequently trigger MAS and inadequate antimicrobial therapy is a common and deadly mistake. 1, 2 Do not delay treatment while awaiting infection workup results, as early intervention is crucial to prevent irreversible organ damage. 2

First-Line Treatment Approach

High-Dose Glucocorticoids (Cornerstone Therapy)

• Initiate intravenous methylprednisolone at 15-30 mg/kg/day (maximum 1g/infusion) for 3-5 consecutive days immediately upon diagnosis. 2 This remains the cornerstone of MAS treatment, with 97.7% of MAS patients receiving glucocorticoids. 2

• The benefits of glucocorticoids for MAS outweigh their risks even in patients whose MAS is triggered by infection, and systemic glucocorticoids are necessary for severely ill patients because of their rapid onset of action. 1

Biologic DMARDs (IL-1 or IL-6 Inhibitors)

• IL-1 or IL-6 inhibitors are conditionally recommended over calcineurin inhibitors alone to achieve inactive disease and resolution of MAS, with no preferred agent between the two. 1 The 2021 ACR guidelines specifically endorse these biologics for MAS in SOJIA. 1

• Anakinra (IL-1 inhibitor) shows complete response rates of 50-100% in published studies, particularly in Still's disease-related MAS, with dosing of 2-10 mg/kg/day subcutaneously in divided doses. 2

• IL-1 and IL-6 inhibitors have proven very helpful in the treatment of systemic JIA and MAS, though monotherapy may not be sufficient for severely ill patients. 1

Cyclosporine A (Early Addition for Severe Cases)

• Add cyclosporine A within 24-48 hours for severe cases or inadequate initial response, at 2-7 mg/kg/day administered orally or intravenously. 2 Cyclosporine A is the second most frequently used drug after glucocorticoids in clinical practice. 2

• High-dose glucocorticoids cannot control hyperinflammation in a significant proportion of patients, making early addition of cyclosporine A critical. 2

Combination Therapy Strategy

Biologic DMARDs combined with glucocorticoids and calcineurin inhibitors may be necessary to control MAS in some patients, as monotherapy is often insufficient for severely ill presentations. 1 For severe MAS or rapid deterioration, use combination therapy from the start including high-dose methylprednisolone, cyclosporine A, and consider adding anakinra early. 2

Critical Care Management

• Transfer patients to ICU immediately if they have grade 3 or higher neurotoxicity, shock or severe organ dysfunction, platelet count <30 g/L, or grade ≥2 cytokine release syndrome with concurrent neurotoxicity. 2

• Reassess clinical status at least every 12 hours to determine the need for escalation of therapy. 2

• Provide supportive care including mechanical ventilation, vasopressor support, renal replacement therapy, transfusion support, and antifungal prophylaxis as needed. 2

Monitoring Treatment Response

• Indicators of treatment response include decreasing ferritin levels, improving cytopenias, resolving coagulopathy, and defervescence. 2

• Continue monitoring inflammatory markers, complete blood counts, coagulation parameters, and organ function tests at least every 12 hours. 2

Subsequent Therapy for Incomplete Response

• For residual arthritis and incomplete response to IL-1 and/or IL-6 inhibitors, biologic DMARDs or conventional synthetic DMARDs are strongly recommended over long-term glucocorticoids. 1 There are many options including adding methotrexate, switching to abatacept or a TNF inhibitor. 1

• Treatment with high-dose glucocorticoids may be required for initial disease control, but subsequent glucocorticoid therapy should be limited to the lowest effective dosage for the shortest duration possible due to effects on bone health and growth. 1

Refractory Cases: Advanced Therapies

• Emapalumab (IFNγ inhibitor) is the only biologic with controlled trial data in MAS, showing >90% complete response rates in patients who failed high-dose glucocorticoids, and is reserved for patients with inadequate response to standard therapy. 2

• JAK inhibitors (ruxolitinib, baricitinib) show efficacy in case reports of chronic-relapsing MAS not responsive to other therapies, with strong rationale based on high expression of genes associated with type I IFN and IFNγ signaling. 2

• Tocilizumab (IL-6 inhibitor) has increasing evidence for efficacy, particularly in MAS associated with systemic rheumatic conditions. 2

Critical Pitfalls to Avoid

• Do not wait for all HLH-2004 criteria to be met before initiating empirical treatment, as early intervention is crucial and delayed diagnosis significantly increases mortality. 2 High suspicion should be maintained in patients with persistent fever, cytopenias, and ferritin >5000 ng/mL. 2

• Do not use glucocorticoids alone in severe cases—add cyclosporine A early, as monotherapy is insufficient for many patients. 2

• MAS is frequently underdiagnosed because its features overlap substantially with severe cytokine release syndrome, sepsis, disease flares, or drug adverse effects. 3

• The mortality rate for children hospitalized with systemic JIA and MAS is estimated to be as high as 6%, but may be even higher based on case series, making aggressive early treatment essential. 1

Long-Term Management After MAS Resolution

• Once inactive disease is attained, taper and discontinue glucocorticoids first before attempting to taper biologic DMARDs or conventional synthetic DMARDs. 1 The risk of flare from well-controlled systemic JIA is considerably outweighed by possible harms from long-term glucocorticoid use, even at low doses. 1

• Tapering and discontinuing biologic DMARDs is conditionally recommended after inactive disease has been attained, though it is unclear how soon after achievement of inactive disease these can be tapered. 1