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
806 drug discovery papers about Macrophage activation syndrome, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
806 drug discovery papers about Macrophage activation syndrome, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-12 | Ruxolitinib combined with corticosteroids for the successful treatment of kawasaki disease-associated macrophage activation syndrome: a case report.
To explore the diagnostic challenges of Kawasaki disease (KD)-associated macrophage activation syndrome (MAS) and the therapeutic value of ruxolitinib combined with corticosteroids. We retrospectively analyzed the clinical data of one pediatric patient with KD-associated MAS and conducted sorting and analysis of relevant published literature. A 14-month-old male infant presented with fever and rash and was diagnosed with severe KD. Despite initial treatment with intravenous immunoglobulin (IVIG) and aspirin, he developed persistent fever, progressive cytopenia, hepatosplenomegaly, hypofibrinogenemia, hyperferritinemia, reduced NK-cell activity, and extremely elevated soluble interleukin-2 receptor (sCD25), fulfilling the HLH-2004 criteria for MAS. He was successfully treated with ruxolitinib plus methylprednisolone, with rapid resolution of fever, recovery of blood counts, and improvement in coagulation and inflammatory markers. KD-associated MAS is rare but life-threatening. Early recognition of warning signs and prompt initiation of ruxolitinib-based combination therapy can effectively control cytokine storm and improve clinical outcomes.
2026-08-11 | The Asia-Pacific League of Associations for Rheumatology Consensus Recommendations on the Management of Systemic Juvenile Idiopathic Arthritis (Juvenile Still's Disease).
The unique characteristics of the Asia Pacific called for the development of pragmatic and viable guidelines for the management of juvenile idiopathic arthritis (JIA). These consensus recommendations represent the second part of the guideline intending to offer an updated and regionally relevant framework for the management of systemic JIA (sJIA)/juvenile Still's disease. A multidisciplinary task force of 35 members from 14 countries, including pediatric and adult rheumatologists as well as patient representatives, was convened. The guideline development followed the GRADE, ADAPTE, and AGREE II frameworks. Relevant international guidelines were critically appraised, and a systematic literature review was performed to address 10 PICO questions. Draft statements were discussed and voted upon using a modified Delphi process, with consensus defined as ≥ 80% agreement. Four overarching principles and eighteen statements, including five statements addressing macrophage activation syndrome (MAS) were formulated. The recommendations align with international guidelines, advocating early use of IL-1/IL-6 inhibitors, avoidance of glucocorticoid monotherapy in sJIA without MAS, promoting tapering of glucocorticoids once inactive disease is achieved, alongside class switching for biologic refractory cases and a treat-to-target approach akin to EULAR/PReS guideline. Additional features include recommending conventional synthetic DMARD when biologics are unavailable and listing the options, acknowledging regional health system heterogeneity in the Asia Pacific, mentioning tapering strategy, discouraging NSAIDs as initial monotherapy, highlighting non-biologic salvage options, and placing less emphasis on sJIA-associated lung diseases. These recommendations provide direction for practitioners caring for sJIA patients in limited resource areas to avoid treatment delay, hence improve overall outcomes. A shared decision approach and treat-to-targets are emphasized.
2026-08-06 | Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome
Abstract Purpose ZNFX1 interferes with early viral replication after exposure to type I interferon, and interacts with mitochondrial antiviral sensors (MAVS) leading to a balanced expression of interferon-stimulated genes (ISGs). ZNFX1 deficiency mimics systemic autoinflammatory diseases and accurate identification may prevent early mortality. We compare a homozygous ZNFX1 frameshift mutation patient to subjects with known interferonopathies. We explore the association between this mutation, unregulated ISGs, and macrophage activation syndrome (MAS). Methods Study participants included our index patient, other patients with well-characterized interferonopathies, and healthy participants. We performed western blotting for ZNFX1 and whole Blood mRNA-seq, RT-qPCR, ELISA, and Olink Proteomics analysis to assess cytokine production and the underlying immune dysregulation. Results Our patient had elevated expression of interferon-inducible genes compared to healthy controls, but levels were comparable to subjects with known interferonopathies. Gene sequencing revealed a novel homozygous ZNFX1 frameshift variant resulting in a truncated protein. Transcriptomic analysis pointed to the top 3 cytokine upstream regulators, tumor necrosis factor (TNF), IL-1β, and interferon-gamma. ZNFX1 deficient patients appear to have a clinical profile that differs from classical type I interferonopathies, including features such as thrombotic microangiopathy (TMA) and a higher frequency of MAS. Conclusions ZNFX1 deficiency is an immune dysregulation disorder characterized by a robust type I interferon signature combined with elevated inflammatory cytokines, leading to severe early-onset multisystem inflammatory disease. Characterizing the immune profile allows targeted short-term treatments that may prolong life.
2026-08-01 | An Unusual Case of Infection-Provoked Macrophage Activation Syndrome in Mixed Connective Tissue Disease
Background Compared to systemic lupus erythematosus and adult-onset Still’s disease, mixed connective tissue disease (MCTD) is rarely associated with macrophage activation syndrome (MAS). Viruses, including cytomegalovirus (CMV), may potentiate MAS,[1] often in conjunction with an underlying connective tissue disease.[1-3] Despite this, reports of infection-provoked MAS in adults with MCTD remain very rare.[2,3] Here we describe a case of MAS in a patient with MCTD and concurrent CMV viremia and Clostridioides difficile colitis. Case Report A 65-year-old male was diagnosed with MCTD after presenting with pulmonary arterial hypertension, presumed glomerulonephritis, Raynaud’s phenomenon, and polyarthritis on a background of coronary artery disease and recent NSTEMI requiring stent placement. Investigation revealed a positive ANA (≥1:640, speckled pattern); high-positive anti-RNP-A, Sm/RNP, Ro60/SSA, Ro52/TRIM21, and SSB; and proteinuria. Right heart catheterization and renal biopsy were deferred given dual-antiplatelet therapy and spontaneous renal recovery. He received methylprednisolone prior to a prednisone taper and initiated mycophenolate mofetil (MMF), hydroxychloroquine, macicentan, and tadalafil. He subsequently presented with watery diarrhea, fever (38.5°C), malaise, weight loss and arthralgia. Infectious work-up revealed CMV viremia (serum viral load >4 million/mL) and C. difficile colitis, for which he initiated ganciclovir and oral vancomycin. He was found to have new bicytopenia (hemoglobin 78 g/L, platelet count 175 ×10^9/L), hyperferritinemia (peak 6751 μg/L), hypertriglyceridemia (3.47 mmol/L), hypofibrinogenemia (nadir 1.0 g/L), and elevated aspartate aminotransferase (101 units/L). His C-reactive protein was 21.0 mg/L (peak) and his complement C3 and C4 were normal. Both hematology and rheumatology were consulted, and the patient was diagnosed with MAS. Bone marrow biopsy was deferred given overwhelming evidence for MAS. His MMF was held for diarrhea, and he was initiated on methylprednisolone (250 mg daily for 3 consecutive days, followed by taper) and anakinra (100 mg subcutaneously daily, titrated to 3-times daily) with clinical and biochemical improvement. Conclusion We found only 2 other published English-language adult cases of MAS in conjunction with MCTD in the context of infection. One case was related to histoplasmosis,[2] and the other to an unspecified infection. [3] It is well known that infections can trigger MAS,[1] and while rare, in the appropriate clinical context, MAS should be considered in patients with MCTD who present with an infection and are not improving with standard treatment and whose biochemical parameters suggest MAS. References [1.] Atteritano M. Eur Rev Medi Pharmacol Sci 2012;16:1414-24. [2.] Kawashima H. Intern Med 2025;64:141-6. [3.] Dhote R. Arthritis Rheum 2003;49:633-9.
2026-08-01 | Macrophage Activation Syndrome in Mixed Connective Tissue Disease: A Case of Multisystem Crisis and Recovery
Background To describe a life-threatening presentation of macrophage activation syndrome (MAS) in a young adult with mixed connective tissue disease (MCTD) with predominant features of SLE, highlighting diagnostic challenges, therapeutic escalation, and the multidisciplinary coordination required for recovery. Case Report Methods: A 28-year-old female with MCTD and Systemic Lupus Erythematosus (SLE) features (managed by Rheumatology in the community), presented to the ER with 3 days of febrile illness, headache and diplopia, chest pain, diarrhea, and profound myalgias. She had been off treatment for several months due to intolerance to Azathioprine and self-discontinuation of Hydroxychloroquine and was recently started on Rinvoq by Dermatology for her only active symptom of inflammatory dermatosis. In the hospital, initial labs revealed bi cytopenia (hemoglobin 111, platelets 128), elevated ferritin (10,827 μg/L), CK (490 U/L), troponin (75 ng/L), and BNP (2497 ng/L). Imaging confirmed myocarditis and MRI brain showed cytotoxic lesion of the corpus callosum (CLOCC). MAS was suspected based on fever, cytopenia’s, hyperferritinemia, and systemic inflammation. Initial treatment included pulse IV methylprednisolone (1 gm daily for 3 days), Anakinra 100 mg SC BID, and continuation of Rinvoq. The patient initially improved but suffered a pulseless electrical activity (PEA) arrest on day 4, requiring 10 minutes of CPR and ICU transfer. Anakinra was escalated, and Emapalumab access was urgently pursued. Results: Following Emapalumab initiation and intensified immunosuppression, the patient stabilized. She was extubated on day 5 post-arrest and transitioned back to the medical unit. Rituximab was added, and hydroxychloroquine was reintroduced. Laboratory markers improved: ferritin decreased to 982 μg/L over 2 weeks, CK and liver enzymes improved, and inflammatory markers resolved. Post ICU stay was complicated by ongoing diplopia and headache, digital gangrene, new proteinuria, and persistent oral ulcerations. Multispecialty involvement included Cardiology, Neurology, Nephrology, Dermatology, and Hematology. Conclusion MAS in MCTD can present subtly before rapid deterioration. Early recognition of hyperferritinemia and cytopenia’s is critical. This case underscores the importance of clinical suspicion, therapeutic escalation, including biologics like anakinra and Emapalumab, and highlights the logistical challenges of accessing rare therapies. Multisystem involvement demands coordinated care, and even with clinical improvement, vigilance is essential due to the risk of delayed complications. We recognize the importance of reporting this case and advocating for the use of these limited access medications that are pivotal for this life-threatening condition.
2026-08-12 | Ruxolitinib combined with corticosteroids for the successful treatment of kawasaki disease-associated macrophage activation syndrome: a case report.
To explore the diagnostic challenges of Kawasaki disease (KD)-associated macrophage activation syndrome (MAS) and the therapeutic value of ruxolitinib combined with corticosteroids. We retrospectively analyzed the clinical data of one pediatric patient with KD-associated MAS and conducted sorting and analysis of relevant published literature. A 14-month-old male infant presented with fever and rash and was diagnosed with severe KD. Despite initial treatment with intravenous immunoglobulin (IVIG) and aspirin, he developed persistent fever, progressive cytopenia, hepatosplenomegaly, hypofibrinogenemia, hyperferritinemia, reduced NK-cell activity, and extremely elevated soluble interleukin-2 receptor (sCD25), fulfilling the HLH-2004 criteria for MAS. He was successfully treated with ruxolitinib plus methylprednisolone, with rapid resolution of fever, recovery of blood counts, and improvement in coagulation and inflammatory markers. KD-associated MAS is rare but life-threatening. Early recognition of warning signs and prompt initiation of ruxolitinib-based combination therapy can effectively control cytokine storm and improve clinical outcomes.
2026-08-11 | The Asia-Pacific League of Associations for Rheumatology Consensus Recommendations on the Management of Systemic Juvenile Idiopathic Arthritis (Juvenile Still's Disease).
The unique characteristics of the Asia Pacific called for the development of pragmatic and viable guidelines for the management of juvenile idiopathic arthritis (JIA). These consensus recommendations represent the second part of the guideline intending to offer an updated and regionally relevant framework for the management of systemic JIA (sJIA)/juvenile Still's disease. A multidisciplinary task force of 35 members from 14 countries, including pediatric and adult rheumatologists as well as patient representatives, was convened. The guideline development followed the GRADE, ADAPTE, and AGREE II frameworks. Relevant international guidelines were critically appraised, and a systematic literature review was performed to address 10 PICO questions. Draft statements were discussed and voted upon using a modified Delphi process, with consensus defined as ≥ 80% agreement. Four overarching principles and eighteen statements, including five statements addressing macrophage activation syndrome (MAS) were formulated. The recommendations align with international guidelines, advocating early use of IL-1/IL-6 inhibitors, avoidance of glucocorticoid monotherapy in sJIA without MAS, promoting tapering of glucocorticoids once inactive disease is achieved, alongside class switching for biologic refractory cases and a treat-to-target approach akin to EULAR/PReS guideline. Additional features include recommending conventional synthetic DMARD when biologics are unavailable and listing the options, acknowledging regional health system heterogeneity in the Asia Pacific, mentioning tapering strategy, discouraging NSAIDs as initial monotherapy, highlighting non-biologic salvage options, and placing less emphasis on sJIA-associated lung diseases. These recommendations provide direction for practitioners caring for sJIA patients in limited resource areas to avoid treatment delay, hence improve overall outcomes. A shared decision approach and treat-to-targets are emphasized.
2026-08-06 | Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome
Abstract Purpose ZNFX1 interferes with early viral replication after exposure to type I interferon, and interacts with mitochondrial antiviral sensors (MAVS) leading to a balanced expression of interferon-stimulated genes (ISGs). ZNFX1 deficiency mimics systemic autoinflammatory diseases and accurate identification may prevent early mortality. We compare a homozygous ZNFX1 frameshift mutation patient to subjects with known interferonopathies. We explore the association between this mutation, unregulated ISGs, and macrophage activation syndrome (MAS). Methods Study participants included our index patient, other patients with well-characterized interferonopathies, and healthy participants. We performed western blotting for ZNFX1 and whole Blood mRNA-seq, RT-qPCR, ELISA, and Olink Proteomics analysis to assess cytokine production and the underlying immune dysregulation. Results Our patient had elevated expression of interferon-inducible genes compared to healthy controls, but levels were comparable to subjects with known interferonopathies. Gene sequencing revealed a novel homozygous ZNFX1 frameshift variant resulting in a truncated protein. Transcriptomic analysis pointed to the top 3 cytokine upstream regulators, tumor necrosis factor (TNF), IL-1β, and interferon-gamma. ZNFX1 deficient patients appear to have a clinical profile that differs from classical type I interferonopathies, including features such as thrombotic microangiopathy (TMA) and a higher frequency of MAS. Conclusions ZNFX1 deficiency is an immune dysregulation disorder characterized by a robust type I interferon signature combined with elevated inflammatory cytokines, leading to severe early-onset multisystem inflammatory disease. Characterizing the immune profile allows targeted short-term treatments that may prolong life.
2026-08-01 | An Unusual Case of Infection-Provoked Macrophage Activation Syndrome in Mixed Connective Tissue Disease
Background Compared to systemic lupus erythematosus and adult-onset Still’s disease, mixed connective tissue disease (MCTD) is rarely associated with macrophage activation syndrome (MAS). Viruses, including cytomegalovirus (CMV), may potentiate MAS,[1] often in conjunction with an underlying connective tissue disease.[1-3] Despite this, reports of infection-provoked MAS in adults with MCTD remain very rare.[2,3] Here we describe a case of MAS in a patient with MCTD and concurrent CMV viremia and Clostridioides difficile colitis. Case Report A 65-year-old male was diagnosed with MCTD after presenting with pulmonary arterial hypertension, presumed glomerulonephritis, Raynaud’s phenomenon, and polyarthritis on a background of coronary artery disease and recent NSTEMI requiring stent placement. Investigation revealed a positive ANA (≥1:640, speckled pattern); high-positive anti-RNP-A, Sm/RNP, Ro60/SSA, Ro52/TRIM21, and SSB; and proteinuria. Right heart catheterization and renal biopsy were deferred given dual-antiplatelet therapy and spontaneous renal recovery. He received methylprednisolone prior to a prednisone taper and initiated mycophenolate mofetil (MMF), hydroxychloroquine, macicentan, and tadalafil. He subsequently presented with watery diarrhea, fever (38.5°C), malaise, weight loss and arthralgia. Infectious work-up revealed CMV viremia (serum viral load >4 million/mL) and C. difficile colitis, for which he initiated ganciclovir and oral vancomycin. He was found to have new bicytopenia (hemoglobin 78 g/L, platelet count 175 ×10^9/L), hyperferritinemia (peak 6751 μg/L), hypertriglyceridemia (3.47 mmol/L), hypofibrinogenemia (nadir 1.0 g/L), and elevated aspartate aminotransferase (101 units/L). His C-reactive protein was 21.0 mg/L (peak) and his complement C3 and C4 were normal. Both hematology and rheumatology were consulted, and the patient was diagnosed with MAS. Bone marrow biopsy was deferred given overwhelming evidence for MAS. His MMF was held for diarrhea, and he was initiated on methylprednisolone (250 mg daily for 3 consecutive days, followed by taper) and anakinra (100 mg subcutaneously daily, titrated to 3-times daily) with clinical and biochemical improvement. Conclusion We found only 2 other published English-language adult cases of MAS in conjunction with MCTD in the context of infection. One case was related to histoplasmosis,[2] and the other to an unspecified infection. [3] It is well known that infections can trigger MAS,[1] and while rare, in the appropriate clinical context, MAS should be considered in patients with MCTD who present with an infection and are not improving with standard treatment and whose biochemical parameters suggest MAS. References [1.] Atteritano M. Eur Rev Medi Pharmacol Sci 2012;16:1414-24. [2.] Kawashima H. Intern Med 2025;64:141-6. [3.] Dhote R. Arthritis Rheum 2003;49:633-9.
2026-08-01 | Macrophage Activation Syndrome in Mixed Connective Tissue Disease: A Case of Multisystem Crisis and Recovery
Background To describe a life-threatening presentation of macrophage activation syndrome (MAS) in a young adult with mixed connective tissue disease (MCTD) with predominant features of SLE, highlighting diagnostic challenges, therapeutic escalation, and the multidisciplinary coordination required for recovery. Case Report Methods: A 28-year-old female with MCTD and Systemic Lupus Erythematosus (SLE) features (managed by Rheumatology in the community), presented to the ER with 3 days of febrile illness, headache and diplopia, chest pain, diarrhea, and profound myalgias. She had been off treatment for several months due to intolerance to Azathioprine and self-discontinuation of Hydroxychloroquine and was recently started on Rinvoq by Dermatology for her only active symptom of inflammatory dermatosis. In the hospital, initial labs revealed bi cytopenia (hemoglobin 111, platelets 128), elevated ferritin (10,827 μg/L), CK (490 U/L), troponin (75 ng/L), and BNP (2497 ng/L). Imaging confirmed myocarditis and MRI brain showed cytotoxic lesion of the corpus callosum (CLOCC). MAS was suspected based on fever, cytopenia’s, hyperferritinemia, and systemic inflammation. Initial treatment included pulse IV methylprednisolone (1 gm daily for 3 days), Anakinra 100 mg SC BID, and continuation of Rinvoq. The patient initially improved but suffered a pulseless electrical activity (PEA) arrest on day 4, requiring 10 minutes of CPR and ICU transfer. Anakinra was escalated, and Emapalumab access was urgently pursued. Results: Following Emapalumab initiation and intensified immunosuppression, the patient stabilized. She was extubated on day 5 post-arrest and transitioned back to the medical unit. Rituximab was added, and hydroxychloroquine was reintroduced. Laboratory markers improved: ferritin decreased to 982 μg/L over 2 weeks, CK and liver enzymes improved, and inflammatory markers resolved. Post ICU stay was complicated by ongoing diplopia and headache, digital gangrene, new proteinuria, and persistent oral ulcerations. Multispecialty involvement included Cardiology, Neurology, Nephrology, Dermatology, and Hematology. Conclusion MAS in MCTD can present subtly before rapid deterioration. Early recognition of hyperferritinemia and cytopenia’s is critical. This case underscores the importance of clinical suspicion, therapeutic escalation, including biologics like anakinra and Emapalumab, and highlights the logistical challenges of accessing rare therapies. Multisystem involvement demands coordinated care, and even with clinical improvement, vigilance is essential due to the risk of delayed complications. We recognize the importance of reporting this case and advocating for the use of these limited access medications that are pivotal for this life-threatening condition.
Access all drug discovery papers and probability of success in trials forecasts:
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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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