RARE DISEASE
Macrophage activation syndrome
Macrophage activation syndrome
Macrophage activation syndrome
Drug discovery
1
drug
With orphan designation
Overview
Macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory condition secondary to rheumatic diseases, infections, or malignancies, characterized by excessive cytokine release, multiorgan dysfunction, and hemophagocytosis. Key features include persistent fever, hepatosplenomegaly, hyperferritinemia (often >684 ng/mL), cytopenia, coagulopathy, and elevated liver enzymes [1][6][16]. Mortality ranges from 20-53% without prompt immunosuppression [5][16]. Diagnosis relies on clinical criteria and exclusion of sepsis [6][10].
Therapies
First-line: High-dose methylprednisolone (30 mg/kg pulses) ± IL-1 inhibitors (anakinra) or IFNγ blockers (emapalumab) [3][8][15].
Refractory cases: Cyclosporine A (2–7 mg/kg/day), etoposide (HLH-94 protocol), or plasma exchange [3][5][15][18].
Emerging options: JAK inhibitors (ruxolitinib) and anti-IL-6 agents (tocilizumab) [8][17].
Categories: rare immunological diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Research Papers
797 drug discovery papers about Macrophage activation syndrome, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
797 drug discovery papers about Macrophage activation syndrome, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-10 | Long-Term Treatment With Emapalumab in an Adult Patient With Refractory Hemophagocytic Lymphohistiocytosis and Systemic Lupus Erythematosus: A Case Report.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive immune activation due to persistently activated cytotoxic lymphocytes and macrophages. HLH can lead to multiorgan dysfunction and can be fatal if left untreated. HLH secondary to autoimmune diseases is referred to as macrophage activation syndrome (MAS). A female Arab Saudi patient in her late 20s with a history of systemic lupus erythematosus (SLE) presented with reduced oral intake, abdominal pain, decreased urine output, tachypnea, shortness of breath, and acute heart failure. MAS secondary to SLE and associated stress cardiomyopathy was suspected. Despite initial treatment with the HLH-94 protocol, the patient showed no improvement and developed Gram-negative septicemia with worsened cytopenia. Emapalumab, a monoclonal antibody that targets interferon gamma (IFN-γ), was introduced as a salvage therapy, resulting in rapid clinical and biochemical improvement, including normalization of cardiac function. The patient received emapalumab for around 17 months, with good tolerability apart from a brief period of CMV reactivation, achieving sustained remission. Following discontinuation, HLH recurred in the context of newly diagnosed myelodysplastic syndrome and was refractory to conventional therapy but responded again to emapalumab retreatment. At the time of last follow-up, the patient remained clinically stable with no evidence of active HLH while continuing emapalumab therapy in the context of ongoing treatment for her underlying conditions. This case report highlights the potential of emapalumab as an effective therapeutic option for the treatment of relapsed/refractory HLH in adults, including in SLE- and malignancy-associated disease not responding to conventional therapy. It supports its role in achieving rapid disease control, enabling prolonged remission with extended use, and allowing successful retreatment in recurrent HLH, including in high-risk settings with poor outcomes such as malignancy-associated HLH.
2026-07-07 | Two- and 3-year outcomes of the childhood arthritis and rheumatology research alliance FiRst Line Options for sJIA Treatment (FROST) trial.
Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disease associated with substantial morbidity, including macrophage activation syndrome (MAS), sJIA-associated lung disease, and glucocorticoid (GC)-related toxicity. CARRA's FiRst Line Options for sJIA Treatment (FROST) study demonstrated favorable short-term outcomes with early biologic therapy, but long-term outcomes have not yet been described. Patients with new-onset sJIA enrolled in FROST (2016-2019) were followed longitudinally through the CARRA Registry. Four consensus treatment plans (CTPs) were evaluated, including IL-1 inhibition (either anakinra or canakinumab), IL-6 inhibition (tocilizumab), and two non-biologic arms (methotrexate or GC monotherapy). Long-term follow-up occurred through 36 months. The primary outcome was achievement of clinical inactive disease (CID) by Wallace/ACR provisional criteria without concurrent GC use at 24 and 36 months. Secondary outcomes included CID irrespective of GC use, cJADAS-10 ≤ 2.5 without fever, medication utilization, and adverse events. Adverse events were expressed as events per 100 person-years. Seventy-three patients were enrolled; 87.6% initiated biologic therapy making comparison to non-biologic therapy infeasible. At 24 and 36 months, 41 and 32 patients, respectively, had evaluable data for the primary outcome. CID without GC use was achieved by 58.5% of patients at 24 months and 65.5% at 36 months. At both time points, over 80% of patients achieved cJADAS-10 ≤ 2.5 without fever and without GC use. Nearly all patients were off GCs at 24 and 36 months (> 90%). The cumulative proportion of patients achieving CID at any time during follow-up increased to 78.8% by 24 months and 87.6% by 36 months. At last follow-up, 42.5% of patients were off all disease-modifying antirheumatic drugs (DMARDs). Over 228.2 person-years of observation, serious adverse events occurred at a rate of 6.6 per 100 person-years; MAS was the most common SAE. No cases of sJIA-associated lung disease were identified. Although results were limited by loss to follow-up, patients enrolled in FROST demonstrated increasing rates of CID and high rates of glucocorticoid discontinuation during long-term follow-up. Serious adverse events were uncommon and largely related to disease activity. These findings support early biologic therapy as an effective and durable first-line strategy for sJIA. Not applicable.
2026-07-06 | Macrophage activation syndrome triggered by Candida parapsilosis-related cochlear implant infection.
Cochlear implant-related infections may rarely lead to life-threatening systemic complications. Macrophage Activation Syndrome (MAS) is a severe and potentially fatal hyperinflammatory condition. MAS associated with CI infection has not been previously reported in pediatric patients. We present a 13-year-old female patient who developed MAS secondary to Candida parapsilosis-related sepsis associated with cochlear implant (CI). Despite broad-spectrum antibacterial and antifungal therapy, the patient's clinical course deteriorated with pancytopenia, hyperferritinemia, and acute liver failure. She fulfilled HLH-2004 criteria and was diagnosed with MAS. Multidisciplinary treatment approach included plasmapheresis, high-dose pulse corticosteroids and CI explantation, resulted in clinical recovery. Implant site cultures revealed that Candida parapsilosis, a fungal pathogen known for biofilm formation and implant-related infections. Following explantation, the patient showed gradual improvement with immunosuppressive therapy and supportive care. Successful cochlear implant reimplantation was performed two months later. CI-related infections and related systemic complications are rare but severe. This is the first reported pediatric case of MAS triggered by cochlear implant-related sepsis. Early recognition of MAS and multidisciplinary management are essential to improve outcome and survival.
2026-07-10 | Long-Term Treatment With Emapalumab in an Adult Patient With Refractory Hemophagocytic Lymphohistiocytosis and Systemic Lupus Erythematosus: A Case Report.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive immune activation due to persistently activated cytotoxic lymphocytes and macrophages. HLH can lead to multiorgan dysfunction and can be fatal if left untreated. HLH secondary to autoimmune diseases is referred to as macrophage activation syndrome (MAS). A female Arab Saudi patient in her late 20s with a history of systemic lupus erythematosus (SLE) presented with reduced oral intake, abdominal pain, decreased urine output, tachypnea, shortness of breath, and acute heart failure. MAS secondary to SLE and associated stress cardiomyopathy was suspected. Despite initial treatment with the HLH-94 protocol, the patient showed no improvement and developed Gram-negative septicemia with worsened cytopenia. Emapalumab, a monoclonal antibody that targets interferon gamma (IFN-γ), was introduced as a salvage therapy, resulting in rapid clinical and biochemical improvement, including normalization of cardiac function. The patient received emapalumab for around 17 months, with good tolerability apart from a brief period of CMV reactivation, achieving sustained remission. Following discontinuation, HLH recurred in the context of newly diagnosed myelodysplastic syndrome and was refractory to conventional therapy but responded again to emapalumab retreatment. At the time of last follow-up, the patient remained clinically stable with no evidence of active HLH while continuing emapalumab therapy in the context of ongoing treatment for her underlying conditions. This case report highlights the potential of emapalumab as an effective therapeutic option for the treatment of relapsed/refractory HLH in adults, including in SLE- and malignancy-associated disease not responding to conventional therapy. It supports its role in achieving rapid disease control, enabling prolonged remission with extended use, and allowing successful retreatment in recurrent HLH, including in high-risk settings with poor outcomes such as malignancy-associated HLH.
2026-07-07 | Two- and 3-year outcomes of the childhood arthritis and rheumatology research alliance FiRst Line Options for sJIA Treatment (FROST) trial.
Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disease associated with substantial morbidity, including macrophage activation syndrome (MAS), sJIA-associated lung disease, and glucocorticoid (GC)-related toxicity. CARRA's FiRst Line Options for sJIA Treatment (FROST) study demonstrated favorable short-term outcomes with early biologic therapy, but long-term outcomes have not yet been described. Patients with new-onset sJIA enrolled in FROST (2016-2019) were followed longitudinally through the CARRA Registry. Four consensus treatment plans (CTPs) were evaluated, including IL-1 inhibition (either anakinra or canakinumab), IL-6 inhibition (tocilizumab), and two non-biologic arms (methotrexate or GC monotherapy). Long-term follow-up occurred through 36 months. The primary outcome was achievement of clinical inactive disease (CID) by Wallace/ACR provisional criteria without concurrent GC use at 24 and 36 months. Secondary outcomes included CID irrespective of GC use, cJADAS-10 ≤ 2.5 without fever, medication utilization, and adverse events. Adverse events were expressed as events per 100 person-years. Seventy-three patients were enrolled; 87.6% initiated biologic therapy making comparison to non-biologic therapy infeasible. At 24 and 36 months, 41 and 32 patients, respectively, had evaluable data for the primary outcome. CID without GC use was achieved by 58.5% of patients at 24 months and 65.5% at 36 months. At both time points, over 80% of patients achieved cJADAS-10 ≤ 2.5 without fever and without GC use. Nearly all patients were off GCs at 24 and 36 months (> 90%). The cumulative proportion of patients achieving CID at any time during follow-up increased to 78.8% by 24 months and 87.6% by 36 months. At last follow-up, 42.5% of patients were off all disease-modifying antirheumatic drugs (DMARDs). Over 228.2 person-years of observation, serious adverse events occurred at a rate of 6.6 per 100 person-years; MAS was the most common SAE. No cases of sJIA-associated lung disease were identified. Although results were limited by loss to follow-up, patients enrolled in FROST demonstrated increasing rates of CID and high rates of glucocorticoid discontinuation during long-term follow-up. Serious adverse events were uncommon and largely related to disease activity. These findings support early biologic therapy as an effective and durable first-line strategy for sJIA. Not applicable.
2026-07-06 | Macrophage activation syndrome triggered by Candida parapsilosis-related cochlear implant infection.
Cochlear implant-related infections may rarely lead to life-threatening systemic complications. Macrophage Activation Syndrome (MAS) is a severe and potentially fatal hyperinflammatory condition. MAS associated with CI infection has not been previously reported in pediatric patients. We present a 13-year-old female patient who developed MAS secondary to Candida parapsilosis-related sepsis associated with cochlear implant (CI). Despite broad-spectrum antibacterial and antifungal therapy, the patient's clinical course deteriorated with pancytopenia, hyperferritinemia, and acute liver failure. She fulfilled HLH-2004 criteria and was diagnosed with MAS. Multidisciplinary treatment approach included plasmapheresis, high-dose pulse corticosteroids and CI explantation, resulted in clinical recovery. Implant site cultures revealed that Candida parapsilosis, a fungal pathogen known for biofilm formation and implant-related infections. Following explantation, the patient showed gradual improvement with immunosuppressive therapy and supportive care. Successful cochlear implant reimplantation was performed two months later. CI-related infections and related systemic complications are rare but severe. This is the first reported pediatric case of MAS triggered by cochlear implant-related sepsis. Early recognition of MAS and multidisciplinary management are essential to improve outcome and survival.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Macrophage activation syndrome.
1 orphan drug designation for Macrophage activation syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
dusquetide | peptides | FDA | 2016-08-10 | — | Soligenix, Inc. |
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