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:
categories:
Small molecules
proteins
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.
2026-06-08 | Dynamic hyperinflammatory response assessment using HIC scores in COVID-19: application to a large series of patients receiving anakinra.
Hyperinflammatory responses substantially contribute to morbidity and mortality in severe COVID-19 and share features with secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome. The Hyperinflammation in COVID-19 (HIC) criteria allow early diagnosis and may provide a framework for dynamic treatment monitoring. We retrospectively analyzed 218 hospitalized patients with hyperinflammation (HIC ≥35) who received anakinra at a tertiary referral center. The daily anakinra dose (100-800 mg/day, administered intravenously or subcutaneously) was adjusted according to clinical and laboratory parameters. The primary outcome was in-hospital mortality. Secondary outcomes included time to ≥50% CRP reduction, ICU admission, mechanical ventilation, and dynamic changes in ΔHIC and inflammatory biomarkers. Overall mortality was 12.8%. Survivors achieved earlier CRP reduction than non-survivors (3.1 vs. 4.7 days) and showed a progressive decline in HIC, whereas non-survivors had persistently elevated or rising scores. Divergence in ΔHIC and other parameters, including neutrophil count, D-dimer, LDH, procalcitonin, and creatine kinase, emerged within 3-4 days. ROC analysis demonstrated that HIC on the day of anakinra initiation and at the final assessment discriminated survivors from non-survivors (AUC 0.75, p < 0.001; cut-offs 70.8 and 66.5, with high sensitivity but moderate specificity), whereas baseline and first-response-day HIC had limited predictive value (AUC approximately 0.50-0.55) . These findings support the HIC score as both a diagnostic and dynamic monitoring tool during IL-1 blockade. Initiating anakinra when HIC is ≥35 but <70, and reassessing treatment response after 3-4 days using ΔHIC together with CRP kinetics, may help optimize outcomes.
2026-04-21 | Therapeutic challenges of concurrent pneumonia and disease flare in a patient with Still’s disease and recurrent macrophage activation syndrome
Introduction Still’s disease belongs to non-familial autoinflammatory systemic disorders. Prior distinction of this condition into two separate entities: the systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), is obsolete, and European Alliance of Associations for Rheumatology recommends that it should be considered as one disease. Case description Patient at age 30, diagnosed with sJIA at 4. The first treatment was high doses of glucocorticosteroids (GCs). At that time, the patient 3 times develop macrophage activation syndrome (MAS). Since 2016, methotrexate (MTX) was prescribed, and in 2022, leflunomide was added as a second drug, but the patients took them irregularly. In 2022, due to a persistent subfebrile state and recurrent arthritis, he was qualified for treatment with tocilizumab at a dose of 400 mg applied in infusions every 4 weeks. Due to a remission state since 2023 multiple attempts to prolong the time between applications were made, but they failed. Finally, in 2025, the duration between dosages was successfully extended to 8 weeks. During therapy, the prior treatment with MTX was recommended but not taken by patients. In January 2026, the patient reported pain in multiple joints, fever, sore throat and rash on his trunk. In addition, patient complains of severe pain in his chest. In laboratory tests, the inflammatory indicators were very high. In the high-resolution computed tomography of the chest, the symptoms of pneumonia were described. Treatment with levofloxacin and a pulse of i.v. methylprednisolone has been introduced with subsequent treatment with prednisolone at a dose 1 mg/kg/day. The regression of changes in the lungs was achieved, the fever did not subside, and inflammatory indicators were still high, pointing to the development of MAS. After administration of tocilizumab, due anakinra was not available, complete remission was achieved. Although the interval from the end of pneumonia treatment was only one week. Due to the reluctance to use MTX, treatment with cyclosporine at a dose of 3 mg/kg/day was proposed. Conclusions The occurrence of severe pneumonia raises concerns about the safety of further tocilizumab treatment. A possible therapeutic option for this patient is interleukin-1 (IL-1) blockade, e.g. anakinra, which, according to the recommendations of the British Society for Rheumatology, is preferred in severe systemic disease over IL-6 blockade. In addition, it has been proven to be safe to use anakinra even in patients with sepsis, so it could be a therapeutic option in this case. Similar data for the use of tocilizumab in bacterial infection is lacking.
2026-03-06 | Macrophage Activation Syndrome and Acute Kidney Injury in Adult-Onset Still’s Disease Despite IL-6 Inhibition: Managed with Intravenous Anakinra
Abstract This report describes a rare case of adult-onset Still’s disease (AOSD) complicated by macrophage activation syndrome (MAS) and acute kidney injury (AKI), despite ongoing interleukin-6 (IL-6) inhibition. The case highlights the diagnostic challenges of MAS in patients receiving IL-6 blockade, particularly in the absence of advanced cytokine or natural killer-cell testing. Timely ferritin monitoring was crucial in confirming MAS. Successful management with corticosteroids and intravenous anakinra prevented the need for dialysis, even in the context of a suspected infection. Only twelve cases of AOSD associated with AKI have been reported in the medical literature as of 2023. Cases of MAS have also been reported in patients receiving biological therapies.
2026-02-13 | [Macrophage activation syndrome in a young patient with polymyositis].
Haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is a life-threatening condition characterised by systemic hyperinflammation and is often triggered by infections, malignancies, or autoimmune disease. The HScore is a diagnostic tool used to estimate the likelihood of HLH/MAS based on clinical, biochemical, and histological findings. This case describes a patient with polymyositis developing MAS, indicated by an HScore of 219. He was treated with IV anakinra, steroids, and immunoglobulin, leading to significant improvement. This case emphasises the importance of early MAS recognition and timely intervention in critical conditions.
small molecules
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.
2026-08-06 | 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 | Systemic JIA with Macrophage Activation Syndrome Complicated by Drug-Induced Liver Injury
Background Systemic juvenile idiopathic arthritis (sJIA) is an autoinflammatory condition that presents diagnostic and therapeutic challenges, especially when complicated by macrophage activation syndrome (MAS) - a life-threatening hyperinflammatory syndrome. Standard therapies for MAS secondary to sJIA include interleukin-1 (IL-1) inhibitors anakinra and canakinumab.[1] Reversible drug induced liver injury from anakinra and canakinumab has been reported, occurring in up to 10% of patients.[2] Specifically, with canakinumab, elevations in hepatic enzymes have been reported in up to 5% but rarely severe.[3] This case highlights the challenges of diagnosis and management for MAS in sJIA with concurrent drug-induced liver injury. Case Report A 16-year-old male, diagnosed with sJIA at age 13, initially presented with quotidian fever, evanescent rash, hepatosplenomegaly and polyarthritis, with no MAS... Initial treatment included prednisone, naproxen and tocilizumab. Due to persistent rash and arthritis, his therapy was changed to anakinra 100mg daily. One year later, he developed pharyngitis and fevers, progressing over 2 weeks into fulminant MAS with unremitting fevers, and supportive labs (Figure 1). His hepatic enzymes remained normal throughout. He stabilized with pulsed methylprednisolone and increasing anakinra to 200mg (3mg/kg). One month later, he developed significant liver injury, with transaminitis and mildly elevated unconjugated bilirubin. Workup revealed no concurrent infection, fever/sJIA flare, or other etiology. His presentation was most consistent with drug-induced liver injury, and anakinra was discontinued. Canakinumab started at 300 mg every 4 weeks. This allowed for prednisone tapering to 10mg over 3 months. However, a progressive transaminitis recurred, spiking 2-3 weeks following each canakinumab administration. During treatment, the patient had no symptoms of sJIA with normal CRP and cell counts. After 3 doses of canakinumab, he developed jaundice, elevated INR and elevated conjugated bilirubin with a peak ALT of 3000 U/L. Liver biopsy demonstrated features of drug-induced liver injury and hemophagocytosis, suggesting a possible mixed presentation with underlying sJIA disease activity and residual MAS. However, he remained afebrile with no signs of sJIA disease activity. Canakinumab was discontinued and 1 month later he started tofacitinib for breakthrough arthritis while on 10mg of prednisone. Two months later, he remains asymptomatic from sJIA and his liver injury has been resolved. His CRP is only mildly elevated on tofacitinib monotherapy. Conclusion This case represents the first detailed description of reversible severe liver injury associated with canakinumab in sJIA complicated with MAS. On tofacitinib, the patient was able to effectively recover from the liver injury and taper off corticosteroid. References [1.] Baldo F. Rheumatology 2025;64:32-44. [2.] Martins FR. Pediatr Rheumatol 2023;21:112. [3.] Ruperto N. Ann Rheum Dis 2018;77:1710-9.
2026-07-28 | GM-CSF-IRF5 Axis as a Therapeutic Target in TLR7-Mediated Macrophage Activation Syndrome 2309192
Abstract Introduction Macrophage Activation Syndrome (MAS) is a severe systemic inflammatory disorder linked to autoimmune diseases like sJIA. It involves macrophage hyperactivation, causing tissue damage, multi-organ failure, and hematopoietic issues. Overexpression of Toll-like receptor 7 (TLR7) has been associated with MAS. Increased GM-CSF levels and IRF5 activation observed in TLR7.1 transgenic mice suggest the GM-CSF-IRF5 pathway’s role in TLR7-driven MAS. Methods WT, Irf5—/—, and GM-CSF—/—mice received topical R848 treatment to activate TLR7. Flow cytometry and imaging flow cytometry were used to quantify blood and splenic Ly6C^hi monocytes and inflammatory hemophagocytes (iHPCs). Red blood cell and platelet counts were measured with the HEMAVET analyzer. To assess disease severity, WT, TLR7.1, TLR7.1Irf5+/—, TLR7.1Irf5—/—, TLR7.1GM-CSF+/—, TLR7.1GM-CSF—/— mice were evaluated. Cytokine levels (GM-CSF, IL-12, IL-6, TNFα) were measured using LegendPlex assays across all groups. Results Topical R848 in WT mice mimicked the TLR7.1 transgenic phenotype, with significant expansion of Ly6C^hi monocytes and iHPCs, contributing to dysregulated hematopoiesis and anemia. These effects were attenuated in Irf5—/— and GM-CSF+/— mice. TLR7.1Irf5+/— and TLR7.1Irf5—/— mice showed reduced GM-CSF levels.GM-CSF deficiency partially protected against early MAS symptoms, with age-dependent effects. Irf5 deficiency resulted in a more profound rescue, markedly decreasing Ly6C^hi monocytes and iHPCs, and fully preventing anemia and thrombocytopenia, thereby restoring hematopoietic balance. Conclusion TLR7 overexpression drives excessive GM-CSF production, which in turn promotes IRF5 activation and expansion of Ly6C^hi monocytes. These cells differentiate into iHPCs, contributing to anemia and inflammatory pathology in MAS. Targeting the GM-CSF—IRF5 axis offers a promising therapeutic strategy for MAS and related autoimmune diseases. Funding Source 5R01AR076242-05 Topic Categories Basic Autoimmunity (BA)
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.
cell therapies
2025-09-01 | Allogeneic haematopoietic stem cell transplantation for severe Still's disease: a retrospective report of three paediatric patients.
Severe forms of systemic JIA (sJIA), also called paediatric-onset Still's disease are associated with two major life-threatening complications: macrophage activation syndrome (MAS) and severe lung disease. Patients are usually resistant to conventional synthetic (cs) DMARDs, biologic (b) DMARDs, and targeted synthetic (ts) DMARDs. Recently, allogeneic haematopoietic stem cell transplantation (HSCT) has been performed in a small number of patients with refractory and life-threatening disease. We aimed to report outcomes and complications of allogeneic HSCT in patients with severe, refractory sJIA treated at our centre. We conducted a retrospective, observational, single-centre study in a tertiary paediatric immunology care centre (Necker Hospital, Paris, France). We report three sJIA patients who underwent allogeneic HSCT at a median age of 3.5 years. All had recurrent MAS; two had lung disease and the HLA-DRB1*15 haplotype, associated with severe delayed hypersensitivity to IL-1/IL-6 inhibitors. Donors were matched sibling donors for the first and third patient, and matched unrelated donor for the second patient. They presented multiple post-graft complications: graft-vs-host disease, infections, thrombotic microangiopathy and severe inflammatory complications on previously affected organs, such as skin and lungs. At a median follow-up of 22 months (20-33) after transplantation, they were all in remission with full-donor chimerism and were off immunosuppressive treatment. Allogeneic HSCT can be an effective salvage therapy in patients with refractory sJIA. However, the risk of post-transplant endothelial complications and severe inflammation in previously affected organs, such as joints, skin and lungs deserves particular attention.
2025-06-01 | POS1430 GENETIC LANDSCAPE OF ADULT-ONSET STILL'S DISEASE WITH MACROPHAGE ACTIVATION SYNDROME: IDENTIFYING KEY RISK LOCI FOR DISEASE MECHANISMS AND PERSONALIZED TREATMENT
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe, life-threatening systemic hyperinflammatory syndromes. They can arise from genetic defects as well as various triggers, including infections, malignancies, and autoimmune diseases. MAS is most recognised and best studied in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Currently, research on the underlying pathogenesis of MAS and its treatment options remains insufficient. Recently, the field of genomics has garnered increasing attention. The objective of this study is to identify the genetic variants associated with AOSD-MAS susceptibility and to elucidate their connections to specific target genes. Such insights are critical for advancing the clinical translation of genetic discoveries, thereby enhancing the accuracy of diagnostic genetic screenings and informing personalized therapeutic strategies. In this study, we performed whole-exome sequencing (WES) on a cohort of AOSD patients to identify potential genetic variations, followed by Sanger sequencing for validation. RNA sequencing (RNA-seq) was conducted to explore gene expression profiles. Statistical analyses were carried out using Fisher's exact test (two-sided) to assess associations, and survival analysis was employed to evaluate outcomes. This study investigated the genetic predisposition of AOSD-MAS, highlighting the critical involvement of known causative genes for primary HLH (pHLH-KG) and the candidate genes in AOSD-MAS. Among the 72 AOSD-MAS patients, 19 individuals (19/72, 26.39%) harbored mutations in pHLH-KG genes, including LYST, PRF1, STX11, UNC13D, NLRC4, STXBP2, AP3B1, CTPS1, RASGRP1, NCKAP1L, and RC3H1. Gene level comparisons demonstrated that ADGRE2, TGFB1, C6, IKZF3, MPO, POLD1, LIFR, IL15RA, and FANCC were significantly enriched in AOSD-MAS compared to AOSD without MAS (AOSD-nMAS), with notable differences (log2OR > 1 or infinite, p-value < 0.05). At the variant level, significant differences were observed for LYST p.I2666N, STX11 p.A125V, POLA1 p.V539M, LRBA p.E88A, ERCC4 p.G912R, and ADGRE2 p.C29Y (p-value < 0.05). These findings strongly suggest that ADGRE2 plays a pivotal role in the pathogenesis of AOSD-MAS. Additionally, we also conducted gene-phenotype correlation analysis, which revealed that CSF2RB and MECOM were significantly more prominent in refractory AOSD-MAS. In conclusion, the potential synergistic interactions among these genes may contribute critically to the development of AOSD-MAS. Our study identified mutations in known HLH-associated genes as well as new candidate genes in AOSD-MAS through WES. Gene-phenotype correlation analysis revealed differences in gene profiles across different clinical phenotypes, providing insights for the precision therapies for AOSD-MAS. NIL. NIL. None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
2025-03-07 | Influence of CAR T-cell therapy associated complications.
Since the introduction of chimeric antigen receptor (CAR) T-cell therapy, it has elicited an immense response in both targeted and residual cancers. Its clinical efficacy is often accompanied by a group of side effects that may become serious because of factors such as tumor burden, the extent of lymphodepletion, and the type of co-stimulus. It is also crucial to know the common toxicities associated with CAR T-cell therapy, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cardiotoxicity, metabolic disorders, pulmonary toxicity, macrophage activation syndrome (MAS), prolonged cytopenia, coagulation disorders, and potential off-target effects on various organs. If not well managed, these can be fatal. However, knowledge about molecular pathways, calcineurin inhibitors, IL-6 receptor antagonists, steroids, suppression of nitric oxide synthase, various therapeutic approaches, and other recent advances have been developed to mitigate the fatal results of various short-term and chronic adverse events related to CAR T-cell therapy. This study provides a comprehensive perspective on contemporary management strategies and presumed causative processes of CAR T-cell-related adverse effects, albeit with several limitations. When CAR T-cell complications, costs, and challenges of toxicity management are properly considered, the CAR T-cell therapy of the future will include a number of toxicity-escaping options.
2024-08-08 | Salvage Therapy and Allogeneic Hematopoietic Cell Transplantation for the Severe Cytokine Storm Syndrome of Hemophagocytic Lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) can be considered as a severe cytokine storm syndrome disorder. HLH typically manifests as a life-threatening inflammatory syndrome characterized by fevers, cytopenias, hepatosplenomegaly, and various other accompanying manifestations such as coagulopathy, hepatitis or liver failure, seizures or altered mental status, and even multi-organ failure. Standard up-front treatments do not always bring HLH into remission or maintain adequate response, and salvage or alternative therapies are often needed. For patients with genetic diseases that cause HLH, curative allogeneic hematopoietic cell transplantation is usually offered to prevent future episodes of life-threatening HLH. Here, we will discuss the options and approaches for salvage therapy and hematopoietic cell transplantation for patients with HLH.
2024-06-22 | Optimization Strategies in CAR T-cell Therapy: A Comprehensive Evaluation of Cytopenia, HLH/MAS, and Other Adverse Events.
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative treatment for various hematological malignancies. Still, its remarkable efficacy is accompanied by unique adverse events that must be carefully managed. This comprehensive literature review evaluates the safety profile of CAR T-cell therapy, focusing on cytopenia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), and other potential complications. Cytopenia, characterized by reduced blood cell counts, affects a significant proportion of patients, with rates of anemia, neutropenia, and thrombocytopenia reaching up to 60%, 70%, and 80%, respectively. Risk factors include high tumor burden, prior chemotherapy, and bone marrow involvement. Cytokine release syndrome (CRS) occurs in 13% to 77% of patients and is linked to the cytokine storm induced by CAR T cells, target antigen expression, and preexisting immune dysregulation. Other notable adverse events discussed are cytokine release syndrome, neurotoxicity, and infections. Understanding the mechanisms, risk factors, and management strategies for these adverse events is crucial for optimizing patient outcomes and unlocking the full potential of this revolutionary therapy. The review highlights the need for continued research, interdisciplinary collaboration, and evidence-based approaches to enhance the safety and efficacy of CAR T-cell therapy.
antibodies
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.
2026-08-01 | 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.
2026-07-15 | Hepatic Involvement in Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome: Clinical and Therapeutic Insights From 2 Cases
We read with interest the manuscript entitled "Hepatic Manifestations in Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome" by Eloseily et al,1 describing 4 patients with systemic juvenile idiopathic arthritis (sJIA) complicated by macrophage activation syndrome (MAS) and hepatic involvement and treated with emapalumab. We report our experience with this subgroup of patients, describing 2 cases treated at Meyer Children9s Hospital in which patients experienced multiple hepatic relapses requiring a combined treatment approach.
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.
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2026-03-08 | Is a variant of uncertain significance always 'insignificant'? A systematic review on PRF1 A91V in Hemophagocytic Lymphohistocytosis and comparative analysis with Still's disease.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that may arise secondary to rheumatic diseases such as Still’s disease, where macrophage activation syndrome (MAS) represents its clinical counterpart. The pathogenic significance of the PRF1 A91V variant remains uncertain, although functional data suggest partial perforin dysfunction and a possible contribution to late-onset or atypical HLH. This study aimed to clarify the clinical implications of the PRF1 A91V variant through a systematic review of published HLH and MAS cases and a comparative analysis with a single-center Still’s disease cohort. A total of 20 studies, including 38 individual HLH or MAS cases carrying the PRF1 A91V variant, were identified. The median age at diagnosis was 22 years, and 18.4% of patients were homozygous. Fever (82.6%), splenomegaly (57.9%), and hepatomegaly (36.8%) were the most frequent clinical findings. Anemia (57.1%) and thrombocytopenia (85.7%) were the predominant laboratory abnormalities, accompanied by marked hyperferritinemia (median 9319 ng/mL). Compared with 43 active Still’s disease cases, PRF1-mutated HLH patients showed significantly higher rates of cytopenias, hepatomegaly, and central nervous system involvement, together with substantially elevated ferritin levels (9,193 vs 800 ng/mL, p = 0.0023), whereas C-reactive protein levels were comparable. Receiver-operating characteristic analysis identified a ferritin cutoff of 7000 ng/mL (sensitivity 63.2%, specificity 84.6%) as the optimal discriminator for PRF1 A91V positivity. In multivariate regression, ferritin ≥ 7,000 ng/mL remained the only independent predictor (OR 17.3, 95% CI 2.0–146.3, p = 0.009). Patients carrying the PRF1 A91V variant represent a distinct subgroup within the spectrum of hyperinflammatory syndromes. Extreme hyperferritinemia combined with cytopenias should raise suspicion for perforin-related HLH rather than cytokine-driven MAS or classic Still’s disease. Recognition of this variant as a risk-modifying allele may guide early genetic testing and therapeutic decisions, including consideration of advanced interventions in selected cases. The online version contains supplementary material available at 10.1186/s13023-026-04296-4.
2025-06-27 | Safety and Efficacy of Simultaneous Vaccination with Polysaccharide Conjugate Vaccines Against Pneumococcal (13-Valent Vaccine) and Haemophilus Type B Infections in Children with Systemic Juvenile Idiopathic Arthritis: Prospective Cohort Study.
Background: The introduction of biological drugs into clinical practice for the treatment of children with systemic juvenile idiopathic arthritis (sJIA) allows disease control but increases the risk of infectious events. Infectious events cause immunosuppressive therapy interruptions, leading to disease flare and life-threatening complications, namely macrophage activation syndrome. Our study aimed to evaluate the efficacy and safety of simultaneous vaccination against pneumococcal and Haemophilus influenzae type b (Hib) in children with sJIA. Methods: This study included 100 sJIA patients receiving immunosuppressive therapy who were simultaneously vaccinated against pneumococcal and Haemophilus influenzae type b (Hib) infections. The mean age of disease onset was 5.5 years. The median age at vaccination was 10 ± 4.5 years. Clinical and laboratory parameters of sJIA activity, immunization efficacy, and safety, including anti-SP and anti-Hib IgG antibodies, as well as all vaccination-related adverse events (AEs), were recorded in every patient before, 3 weeks after, and 6 months after vaccination. Results: At the time of vaccination, 29% of patients did not meet the criteria for the inactive disease stage, as defined by C. Wallace: active joints were present in 34.5% of patients, systemic manifestations (rash and/or fever) were present in 41.3%, and 24.2% of patients had solely inflammatory laboratory activity. The protective titer of anti-SP and anti-Hib IgG antibodies was detected in the majority of patients 3 weeks after vaccination (100% and 93%, respectively). The results remained unchanged (99% and 92%, respectively) for 6 months of follow-up, compared to the baseline (91% and 37%, p = 0.000001). Anti-SP IgG and anti-Hib titers raised from 48.3 (18.2; 76.5) and 0.64 (0.3; 3.2) U/mL at the baseline to 103.5 (47.3; 185.4) and 4 (3.5; 4.2) U/mL at D22 and 105 (48.7; 171.8) and 4 (3.8; 4) U/mL (EOS), respectively. Immunosuppressive therapy regimens (combined therapy or biological disease-modifying antirheumatic drug monotherapy) did not influence the immunogenic efficacy of vaccination. The incidence of infectious complications (p = 0.0000001) and antibiotic prescriptions (p = 0.0000001) decreased by more than two times, to 29.9 and 13.8 events per 100 patient months, respectively, within 6 months after vaccination-the average duration of acute infectious events was reduced by five times after immunization (p = 0.0000001). Vaccination did not lead to disease flare: the number of patients with active joints decreased by half compared to the baseline, and the number of patients with systemic manifestations decreased by six times. All vaccine-associated adverse events were considered mild and resolved within 1-2 days. Conclusions: Simultaneous vaccination against pneumococcal and Hib infections in sJIA children is an effective and safe tool that reduces the number and duration of infectious events and does not cause disease flare-ups.
2024-10-29 | Functional role of UNC13D in immune diseases and its therapeutic applications.
UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.
2024-03-15 | Identification of miRNAs that target Fcγ receptor-mediated phagocytosis during macrophage activation syndrome
Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19–related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor–mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B , the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A , the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic–based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.
2019-06-01 | THU0508 CHANGES IN MIR-17–92 CLUSTER EXPRESSION LINK SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS, MONOCYTE-TO-MACROPHAGE DIFFERENTIATION, AND INTERFERON REGULATION
MicroRNAs (miRNAs) are small noncoding RNAs which post-transcriptionally regulate gene expression. The miR-17-92 cluster is well studied in cancer biology and cellular differentiation; its overexpression has been found to serve a major oncogenic role in the targeting and downregulation of tumor-suppressive pathways, such as PTEN or TGFß. Our previous work identified several members of the cluster – miR-18, miR-19a/b, miR-20a, and miR-92a – with significantly higher levels in monocytes from patients with active Systemic Juvenile Idiopathic Arthritis (SJIA). SJIA is a chronic inflammatory disease of childhood with features of autoinflammation, and innate immune cells including monocytes have important roles in disease pathogenesis. Children with SJIA are at risk for life-threatening complications including Macrophage Activation Syndrome (MAS), an episode of overwhelming inflammation characterized by macrophage proliferation and driven by IFNγ. Characterize the regulation of the miR-17-92 cluster, define key targets, and determine the cluster’s role in inflammation and SJIA. MiRNA levels were examined in THP-1 cells, as well as primary human monocytes isolated from healthy donors over the course of the monocyte to monocyte-derived macrophage (MDM) transition. MiR-17, miR-19a, and miR-20a were overexpressed via transfection in CD14+ monocytes for 2 days. Transcriptional profiles were performed using Ampliseq Transcriptome and the Ion Torrent S5 system and analyzed using AltAnalyze. Potential targets of the miR-17-92 cluster determined from sequencing analysis were then validated via dual-luciferase reporter assay. Neither blood monocytes nor fully differentiated THP-1 cells showed significant changes in miR-17-92 levels under standard polarization conditions, including M1, M2a, and M2b conditions, or IL-6 and IL-10 stimulation. The most sizable changes in miR-17-92 levels were found during monocyte to macrophage transition. Interestingly, primary monocytes showed increases in miR-17-92 levels within the first 48 hours of differentiation towards MDM, variable by miRNA and experiment, similar to that seen in SJIA monocytes. In contrast, both PMA-differentiated THP1 cells and fully differentiated MDMs showed decreased miR-17-92 compared to undifferentiated monocytic cells. MiR-17-92 was overexpressed in vitro in primary monocytes to model these early transition changes. Genome-wide transcriptional profiling showed an upregulation of genes involved in Type I and II Interferon pathways, including response to interferon-alpha (adjusted p=2.71x10-12) and interferon-gamma (adjusted p=7.81x10-9). Analysis of genes significantly downregulated by miR-17, miR-19a, or miR-20a identified several putative and previously validated miR-17-92 cluster targets, including ATG5, IFRD2, JAK1, PPARG, and PTPN2 which have interferon-regulatory functions. Dual-luciferase reporter assay experiments support that these genes are direct targets of miR-17, miR-19a, and/or miR-20a. MiR-17-92 cluster members demonstrate initial increase followed by subsequent decrease in expression during 2-week human monocyte to macrophage differentiation. Overexpression of miR-17-92 miRNAs upregulates Type I and II interferon pathway genes, and these miRNAs target multiple genes involved in regulating interferon signaling and/or inflammatory response. Taken together, miR-17-92 cluster overexpression in SJIA monocytes may suggest a more differentiated phenotype, and contribute to IFNγ sensitivity and risk for MAS. None declared
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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.
2026-06-08 | Dynamic hyperinflammatory response assessment using HIC scores in COVID-19: application to a large series of patients receiving anakinra.
Hyperinflammatory responses substantially contribute to morbidity and mortality in severe COVID-19 and share features with secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome. The Hyperinflammation in COVID-19 (HIC) criteria allow early diagnosis and may provide a framework for dynamic treatment monitoring. We retrospectively analyzed 218 hospitalized patients with hyperinflammation (HIC ≥35) who received anakinra at a tertiary referral center. The daily anakinra dose (100-800 mg/day, administered intravenously or subcutaneously) was adjusted according to clinical and laboratory parameters. The primary outcome was in-hospital mortality. Secondary outcomes included time to ≥50% CRP reduction, ICU admission, mechanical ventilation, and dynamic changes in ΔHIC and inflammatory biomarkers. Overall mortality was 12.8%. Survivors achieved earlier CRP reduction than non-survivors (3.1 vs. 4.7 days) and showed a progressive decline in HIC, whereas non-survivors had persistently elevated or rising scores. Divergence in ΔHIC and other parameters, including neutrophil count, D-dimer, LDH, procalcitonin, and creatine kinase, emerged within 3-4 days. ROC analysis demonstrated that HIC on the day of anakinra initiation and at the final assessment discriminated survivors from non-survivors (AUC 0.75, p < 0.001; cut-offs 70.8 and 66.5, with high sensitivity but moderate specificity), whereas baseline and first-response-day HIC had limited predictive value (AUC approximately 0.50-0.55) . These findings support the HIC score as both a diagnostic and dynamic monitoring tool during IL-1 blockade. Initiating anakinra when HIC is ≥35 but <70, and reassessing treatment response after 3-4 days using ΔHIC together with CRP kinetics, may help optimize outcomes.
2026-04-21 | Therapeutic challenges of concurrent pneumonia and disease flare in a patient with Still’s disease and recurrent macrophage activation syndrome
Introduction Still’s disease belongs to non-familial autoinflammatory systemic disorders. Prior distinction of this condition into two separate entities: the systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), is obsolete, and European Alliance of Associations for Rheumatology recommends that it should be considered as one disease. Case description Patient at age 30, diagnosed with sJIA at 4. The first treatment was high doses of glucocorticosteroids (GCs). At that time, the patient 3 times develop macrophage activation syndrome (MAS). Since 2016, methotrexate (MTX) was prescribed, and in 2022, leflunomide was added as a second drug, but the patients took them irregularly. In 2022, due to a persistent subfebrile state and recurrent arthritis, he was qualified for treatment with tocilizumab at a dose of 400 mg applied in infusions every 4 weeks. Due to a remission state since 2023 multiple attempts to prolong the time between applications were made, but they failed. Finally, in 2025, the duration between dosages was successfully extended to 8 weeks. During therapy, the prior treatment with MTX was recommended but not taken by patients. In January 2026, the patient reported pain in multiple joints, fever, sore throat and rash on his trunk. In addition, patient complains of severe pain in his chest. In laboratory tests, the inflammatory indicators were very high. In the high-resolution computed tomography of the chest, the symptoms of pneumonia were described. Treatment with levofloxacin and a pulse of i.v. methylprednisolone has been introduced with subsequent treatment with prednisolone at a dose 1 mg/kg/day. The regression of changes in the lungs was achieved, the fever did not subside, and inflammatory indicators were still high, pointing to the development of MAS. After administration of tocilizumab, due anakinra was not available, complete remission was achieved. Although the interval from the end of pneumonia treatment was only one week. Due to the reluctance to use MTX, treatment with cyclosporine at a dose of 3 mg/kg/day was proposed. Conclusions The occurrence of severe pneumonia raises concerns about the safety of further tocilizumab treatment. A possible therapeutic option for this patient is interleukin-1 (IL-1) blockade, e.g. anakinra, which, according to the recommendations of the British Society for Rheumatology, is preferred in severe systemic disease over IL-6 blockade. In addition, it has been proven to be safe to use anakinra even in patients with sepsis, so it could be a therapeutic option in this case. Similar data for the use of tocilizumab in bacterial infection is lacking.
2026-03-06 | Macrophage Activation Syndrome and Acute Kidney Injury in Adult-Onset Still’s Disease Despite IL-6 Inhibition: Managed with Intravenous Anakinra
Abstract This report describes a rare case of adult-onset Still’s disease (AOSD) complicated by macrophage activation syndrome (MAS) and acute kidney injury (AKI), despite ongoing interleukin-6 (IL-6) inhibition. The case highlights the diagnostic challenges of MAS in patients receiving IL-6 blockade, particularly in the absence of advanced cytokine or natural killer-cell testing. Timely ferritin monitoring was crucial in confirming MAS. Successful management with corticosteroids and intravenous anakinra prevented the need for dialysis, even in the context of a suspected infection. Only twelve cases of AOSD associated with AKI have been reported in the medical literature as of 2023. Cases of MAS have also been reported in patients receiving biological therapies.
2026-02-13 | [Macrophage activation syndrome in a young patient with polymyositis].
Haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is a life-threatening condition characterised by systemic hyperinflammation and is often triggered by infections, malignancies, or autoimmune disease. The HScore is a diagnostic tool used to estimate the likelihood of HLH/MAS based on clinical, biochemical, and histological findings. This case describes a patient with polymyositis developing MAS, indicated by an HScore of 219. He was treated with IV anakinra, steroids, and immunoglobulin, leading to significant improvement. This case emphasises the importance of early MAS recognition and timely intervention in critical conditions.
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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.
2026-08-06 | 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 | Systemic JIA with Macrophage Activation Syndrome Complicated by Drug-Induced Liver Injury
Background Systemic juvenile idiopathic arthritis (sJIA) is an autoinflammatory condition that presents diagnostic and therapeutic challenges, especially when complicated by macrophage activation syndrome (MAS) - a life-threatening hyperinflammatory syndrome. Standard therapies for MAS secondary to sJIA include interleukin-1 (IL-1) inhibitors anakinra and canakinumab.[1] Reversible drug induced liver injury from anakinra and canakinumab has been reported, occurring in up to 10% of patients.[2] Specifically, with canakinumab, elevations in hepatic enzymes have been reported in up to 5% but rarely severe.[3] This case highlights the challenges of diagnosis and management for MAS in sJIA with concurrent drug-induced liver injury. Case Report A 16-year-old male, diagnosed with sJIA at age 13, initially presented with quotidian fever, evanescent rash, hepatosplenomegaly and polyarthritis, with no MAS... Initial treatment included prednisone, naproxen and tocilizumab. Due to persistent rash and arthritis, his therapy was changed to anakinra 100mg daily. One year later, he developed pharyngitis and fevers, progressing over 2 weeks into fulminant MAS with unremitting fevers, and supportive labs (Figure 1). His hepatic enzymes remained normal throughout. He stabilized with pulsed methylprednisolone and increasing anakinra to 200mg (3mg/kg). One month later, he developed significant liver injury, with transaminitis and mildly elevated unconjugated bilirubin. Workup revealed no concurrent infection, fever/sJIA flare, or other etiology. His presentation was most consistent with drug-induced liver injury, and anakinra was discontinued. Canakinumab started at 300 mg every 4 weeks. This allowed for prednisone tapering to 10mg over 3 months. However, a progressive transaminitis recurred, spiking 2-3 weeks following each canakinumab administration. During treatment, the patient had no symptoms of sJIA with normal CRP and cell counts. After 3 doses of canakinumab, he developed jaundice, elevated INR and elevated conjugated bilirubin with a peak ALT of 3000 U/L. Liver biopsy demonstrated features of drug-induced liver injury and hemophagocytosis, suggesting a possible mixed presentation with underlying sJIA disease activity and residual MAS. However, he remained afebrile with no signs of sJIA disease activity. Canakinumab was discontinued and 1 month later he started tofacitinib for breakthrough arthritis while on 10mg of prednisone. Two months later, he remains asymptomatic from sJIA and his liver injury has been resolved. His CRP is only mildly elevated on tofacitinib monotherapy. Conclusion This case represents the first detailed description of reversible severe liver injury associated with canakinumab in sJIA complicated with MAS. On tofacitinib, the patient was able to effectively recover from the liver injury and taper off corticosteroid. References [1.] Baldo F. Rheumatology 2025;64:32-44. [2.] Martins FR. Pediatr Rheumatol 2023;21:112. [3.] Ruperto N. Ann Rheum Dis 2018;77:1710-9.
2026-07-28 | GM-CSF-IRF5 Axis as a Therapeutic Target in TLR7-Mediated Macrophage Activation Syndrome 2309192
Abstract Introduction Macrophage Activation Syndrome (MAS) is a severe systemic inflammatory disorder linked to autoimmune diseases like sJIA. It involves macrophage hyperactivation, causing tissue damage, multi-organ failure, and hematopoietic issues. Overexpression of Toll-like receptor 7 (TLR7) has been associated with MAS. Increased GM-CSF levels and IRF5 activation observed in TLR7.1 transgenic mice suggest the GM-CSF-IRF5 pathway’s role in TLR7-driven MAS. Methods WT, Irf5—/—, and GM-CSF—/—mice received topical R848 treatment to activate TLR7. Flow cytometry and imaging flow cytometry were used to quantify blood and splenic Ly6C^hi monocytes and inflammatory hemophagocytes (iHPCs). Red blood cell and platelet counts were measured with the HEMAVET analyzer. To assess disease severity, WT, TLR7.1, TLR7.1Irf5+/—, TLR7.1Irf5—/—, TLR7.1GM-CSF+/—, TLR7.1GM-CSF—/— mice were evaluated. Cytokine levels (GM-CSF, IL-12, IL-6, TNFα) were measured using LegendPlex assays across all groups. Results Topical R848 in WT mice mimicked the TLR7.1 transgenic phenotype, with significant expansion of Ly6C^hi monocytes and iHPCs, contributing to dysregulated hematopoiesis and anemia. These effects were attenuated in Irf5—/— and GM-CSF+/— mice. TLR7.1Irf5+/— and TLR7.1Irf5—/— mice showed reduced GM-CSF levels.GM-CSF deficiency partially protected against early MAS symptoms, with age-dependent effects. Irf5 deficiency resulted in a more profound rescue, markedly decreasing Ly6C^hi monocytes and iHPCs, and fully preventing anemia and thrombocytopenia, thereby restoring hematopoietic balance. Conclusion TLR7 overexpression drives excessive GM-CSF production, which in turn promotes IRF5 activation and expansion of Ly6C^hi monocytes. These cells differentiate into iHPCs, contributing to anemia and inflammatory pathology in MAS. Targeting the GM-CSF—IRF5 axis offers a promising therapeutic strategy for MAS and related autoimmune diseases. Funding Source 5R01AR076242-05 Topic Categories Basic Autoimmunity (BA)
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.
cell therapies
2025-09-01 | Allogeneic haematopoietic stem cell transplantation for severe Still's disease: a retrospective report of three paediatric patients.
Severe forms of systemic JIA (sJIA), also called paediatric-onset Still's disease are associated with two major life-threatening complications: macrophage activation syndrome (MAS) and severe lung disease. Patients are usually resistant to conventional synthetic (cs) DMARDs, biologic (b) DMARDs, and targeted synthetic (ts) DMARDs. Recently, allogeneic haematopoietic stem cell transplantation (HSCT) has been performed in a small number of patients with refractory and life-threatening disease. We aimed to report outcomes and complications of allogeneic HSCT in patients with severe, refractory sJIA treated at our centre. We conducted a retrospective, observational, single-centre study in a tertiary paediatric immunology care centre (Necker Hospital, Paris, France). We report three sJIA patients who underwent allogeneic HSCT at a median age of 3.5 years. All had recurrent MAS; two had lung disease and the HLA-DRB1*15 haplotype, associated with severe delayed hypersensitivity to IL-1/IL-6 inhibitors. Donors were matched sibling donors for the first and third patient, and matched unrelated donor for the second patient. They presented multiple post-graft complications: graft-vs-host disease, infections, thrombotic microangiopathy and severe inflammatory complications on previously affected organs, such as skin and lungs. At a median follow-up of 22 months (20-33) after transplantation, they were all in remission with full-donor chimerism and were off immunosuppressive treatment. Allogeneic HSCT can be an effective salvage therapy in patients with refractory sJIA. However, the risk of post-transplant endothelial complications and severe inflammation in previously affected organs, such as joints, skin and lungs deserves particular attention.
2025-06-01 | POS1430 GENETIC LANDSCAPE OF ADULT-ONSET STILL'S DISEASE WITH MACROPHAGE ACTIVATION SYNDROME: IDENTIFYING KEY RISK LOCI FOR DISEASE MECHANISMS AND PERSONALIZED TREATMENT
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe, life-threatening systemic hyperinflammatory syndromes. They can arise from genetic defects as well as various triggers, including infections, malignancies, and autoimmune diseases. MAS is most recognised and best studied in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Currently, research on the underlying pathogenesis of MAS and its treatment options remains insufficient. Recently, the field of genomics has garnered increasing attention. The objective of this study is to identify the genetic variants associated with AOSD-MAS susceptibility and to elucidate their connections to specific target genes. Such insights are critical for advancing the clinical translation of genetic discoveries, thereby enhancing the accuracy of diagnostic genetic screenings and informing personalized therapeutic strategies. In this study, we performed whole-exome sequencing (WES) on a cohort of AOSD patients to identify potential genetic variations, followed by Sanger sequencing for validation. RNA sequencing (RNA-seq) was conducted to explore gene expression profiles. Statistical analyses were carried out using Fisher's exact test (two-sided) to assess associations, and survival analysis was employed to evaluate outcomes. This study investigated the genetic predisposition of AOSD-MAS, highlighting the critical involvement of known causative genes for primary HLH (pHLH-KG) and the candidate genes in AOSD-MAS. Among the 72 AOSD-MAS patients, 19 individuals (19/72, 26.39%) harbored mutations in pHLH-KG genes, including LYST, PRF1, STX11, UNC13D, NLRC4, STXBP2, AP3B1, CTPS1, RASGRP1, NCKAP1L, and RC3H1. Gene level comparisons demonstrated that ADGRE2, TGFB1, C6, IKZF3, MPO, POLD1, LIFR, IL15RA, and FANCC were significantly enriched in AOSD-MAS compared to AOSD without MAS (AOSD-nMAS), with notable differences (log2OR > 1 or infinite, p-value < 0.05). At the variant level, significant differences were observed for LYST p.I2666N, STX11 p.A125V, POLA1 p.V539M, LRBA p.E88A, ERCC4 p.G912R, and ADGRE2 p.C29Y (p-value < 0.05). These findings strongly suggest that ADGRE2 plays a pivotal role in the pathogenesis of AOSD-MAS. Additionally, we also conducted gene-phenotype correlation analysis, which revealed that CSF2RB and MECOM were significantly more prominent in refractory AOSD-MAS. In conclusion, the potential synergistic interactions among these genes may contribute critically to the development of AOSD-MAS. Our study identified mutations in known HLH-associated genes as well as new candidate genes in AOSD-MAS through WES. Gene-phenotype correlation analysis revealed differences in gene profiles across different clinical phenotypes, providing insights for the precision therapies for AOSD-MAS. NIL. NIL. None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
2025-03-07 | Influence of CAR T-cell therapy associated complications.
Since the introduction of chimeric antigen receptor (CAR) T-cell therapy, it has elicited an immense response in both targeted and residual cancers. Its clinical efficacy is often accompanied by a group of side effects that may become serious because of factors such as tumor burden, the extent of lymphodepletion, and the type of co-stimulus. It is also crucial to know the common toxicities associated with CAR T-cell therapy, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cardiotoxicity, metabolic disorders, pulmonary toxicity, macrophage activation syndrome (MAS), prolonged cytopenia, coagulation disorders, and potential off-target effects on various organs. If not well managed, these can be fatal. However, knowledge about molecular pathways, calcineurin inhibitors, IL-6 receptor antagonists, steroids, suppression of nitric oxide synthase, various therapeutic approaches, and other recent advances have been developed to mitigate the fatal results of various short-term and chronic adverse events related to CAR T-cell therapy. This study provides a comprehensive perspective on contemporary management strategies and presumed causative processes of CAR T-cell-related adverse effects, albeit with several limitations. When CAR T-cell complications, costs, and challenges of toxicity management are properly considered, the CAR T-cell therapy of the future will include a number of toxicity-escaping options.
2024-08-08 | Salvage Therapy and Allogeneic Hematopoietic Cell Transplantation for the Severe Cytokine Storm Syndrome of Hemophagocytic Lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) can be considered as a severe cytokine storm syndrome disorder. HLH typically manifests as a life-threatening inflammatory syndrome characterized by fevers, cytopenias, hepatosplenomegaly, and various other accompanying manifestations such as coagulopathy, hepatitis or liver failure, seizures or altered mental status, and even multi-organ failure. Standard up-front treatments do not always bring HLH into remission or maintain adequate response, and salvage or alternative therapies are often needed. For patients with genetic diseases that cause HLH, curative allogeneic hematopoietic cell transplantation is usually offered to prevent future episodes of life-threatening HLH. Here, we will discuss the options and approaches for salvage therapy and hematopoietic cell transplantation for patients with HLH.
2024-06-22 | Optimization Strategies in CAR T-cell Therapy: A Comprehensive Evaluation of Cytopenia, HLH/MAS, and Other Adverse Events.
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative treatment for various hematological malignancies. Still, its remarkable efficacy is accompanied by unique adverse events that must be carefully managed. This comprehensive literature review evaluates the safety profile of CAR T-cell therapy, focusing on cytopenia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), and other potential complications. Cytopenia, characterized by reduced blood cell counts, affects a significant proportion of patients, with rates of anemia, neutropenia, and thrombocytopenia reaching up to 60%, 70%, and 80%, respectively. Risk factors include high tumor burden, prior chemotherapy, and bone marrow involvement. Cytokine release syndrome (CRS) occurs in 13% to 77% of patients and is linked to the cytokine storm induced by CAR T cells, target antigen expression, and preexisting immune dysregulation. Other notable adverse events discussed are cytokine release syndrome, neurotoxicity, and infections. Understanding the mechanisms, risk factors, and management strategies for these adverse events is crucial for optimizing patient outcomes and unlocking the full potential of this revolutionary therapy. The review highlights the need for continued research, interdisciplinary collaboration, and evidence-based approaches to enhance the safety and efficacy of CAR T-cell therapy.
antibodies
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.
2026-08-01 | 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.
2026-07-15 | Hepatic Involvement in Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome: Clinical and Therapeutic Insights From 2 Cases
We read with interest the manuscript entitled "Hepatic Manifestations in Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome" by Eloseily et al,1 describing 4 patients with systemic juvenile idiopathic arthritis (sJIA) complicated by macrophage activation syndrome (MAS) and hepatic involvement and treated with emapalumab. We report our experience with this subgroup of patients, describing 2 cases treated at Meyer Children9s Hospital in which patients experienced multiple hepatic relapses requiring a combined treatment approach.
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.
other
2026-03-08 | Is a variant of uncertain significance always 'insignificant'? A systematic review on PRF1 A91V in Hemophagocytic Lymphohistocytosis and comparative analysis with Still's disease.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that may arise secondary to rheumatic diseases such as Still’s disease, where macrophage activation syndrome (MAS) represents its clinical counterpart. The pathogenic significance of the PRF1 A91V variant remains uncertain, although functional data suggest partial perforin dysfunction and a possible contribution to late-onset or atypical HLH. This study aimed to clarify the clinical implications of the PRF1 A91V variant through a systematic review of published HLH and MAS cases and a comparative analysis with a single-center Still’s disease cohort. A total of 20 studies, including 38 individual HLH or MAS cases carrying the PRF1 A91V variant, were identified. The median age at diagnosis was 22 years, and 18.4% of patients were homozygous. Fever (82.6%), splenomegaly (57.9%), and hepatomegaly (36.8%) were the most frequent clinical findings. Anemia (57.1%) and thrombocytopenia (85.7%) were the predominant laboratory abnormalities, accompanied by marked hyperferritinemia (median 9319 ng/mL). Compared with 43 active Still’s disease cases, PRF1-mutated HLH patients showed significantly higher rates of cytopenias, hepatomegaly, and central nervous system involvement, together with substantially elevated ferritin levels (9,193 vs 800 ng/mL, p = 0.0023), whereas C-reactive protein levels were comparable. Receiver-operating characteristic analysis identified a ferritin cutoff of 7000 ng/mL (sensitivity 63.2%, specificity 84.6%) as the optimal discriminator for PRF1 A91V positivity. In multivariate regression, ferritin ≥ 7,000 ng/mL remained the only independent predictor (OR 17.3, 95% CI 2.0–146.3, p = 0.009). Patients carrying the PRF1 A91V variant represent a distinct subgroup within the spectrum of hyperinflammatory syndromes. Extreme hyperferritinemia combined with cytopenias should raise suspicion for perforin-related HLH rather than cytokine-driven MAS or classic Still’s disease. Recognition of this variant as a risk-modifying allele may guide early genetic testing and therapeutic decisions, including consideration of advanced interventions in selected cases. The online version contains supplementary material available at 10.1186/s13023-026-04296-4.
2025-06-27 | Safety and Efficacy of Simultaneous Vaccination with Polysaccharide Conjugate Vaccines Against Pneumococcal (13-Valent Vaccine) and Haemophilus Type B Infections in Children with Systemic Juvenile Idiopathic Arthritis: Prospective Cohort Study.
Background: The introduction of biological drugs into clinical practice for the treatment of children with systemic juvenile idiopathic arthritis (sJIA) allows disease control but increases the risk of infectious events. Infectious events cause immunosuppressive therapy interruptions, leading to disease flare and life-threatening complications, namely macrophage activation syndrome. Our study aimed to evaluate the efficacy and safety of simultaneous vaccination against pneumococcal and Haemophilus influenzae type b (Hib) in children with sJIA. Methods: This study included 100 sJIA patients receiving immunosuppressive therapy who were simultaneously vaccinated against pneumococcal and Haemophilus influenzae type b (Hib) infections. The mean age of disease onset was 5.5 years. The median age at vaccination was 10 ± 4.5 years. Clinical and laboratory parameters of sJIA activity, immunization efficacy, and safety, including anti-SP and anti-Hib IgG antibodies, as well as all vaccination-related adverse events (AEs), were recorded in every patient before, 3 weeks after, and 6 months after vaccination. Results: At the time of vaccination, 29% of patients did not meet the criteria for the inactive disease stage, as defined by C. Wallace: active joints were present in 34.5% of patients, systemic manifestations (rash and/or fever) were present in 41.3%, and 24.2% of patients had solely inflammatory laboratory activity. The protective titer of anti-SP and anti-Hib IgG antibodies was detected in the majority of patients 3 weeks after vaccination (100% and 93%, respectively). The results remained unchanged (99% and 92%, respectively) for 6 months of follow-up, compared to the baseline (91% and 37%, p = 0.000001). Anti-SP IgG and anti-Hib titers raised from 48.3 (18.2; 76.5) and 0.64 (0.3; 3.2) U/mL at the baseline to 103.5 (47.3; 185.4) and 4 (3.5; 4.2) U/mL at D22 and 105 (48.7; 171.8) and 4 (3.8; 4) U/mL (EOS), respectively. Immunosuppressive therapy regimens (combined therapy or biological disease-modifying antirheumatic drug monotherapy) did not influence the immunogenic efficacy of vaccination. The incidence of infectious complications (p = 0.0000001) and antibiotic prescriptions (p = 0.0000001) decreased by more than two times, to 29.9 and 13.8 events per 100 patient months, respectively, within 6 months after vaccination-the average duration of acute infectious events was reduced by five times after immunization (p = 0.0000001). Vaccination did not lead to disease flare: the number of patients with active joints decreased by half compared to the baseline, and the number of patients with systemic manifestations decreased by six times. All vaccine-associated adverse events were considered mild and resolved within 1-2 days. Conclusions: Simultaneous vaccination against pneumococcal and Hib infections in sJIA children is an effective and safe tool that reduces the number and duration of infectious events and does not cause disease flare-ups.
2024-10-29 | Functional role of UNC13D in immune diseases and its therapeutic applications.
UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.
2024-03-15 | Identification of miRNAs that target Fcγ receptor-mediated phagocytosis during macrophage activation syndrome
Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19–related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor–mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B , the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A , the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic–based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.
2019-06-01 | THU0508 CHANGES IN MIR-17–92 CLUSTER EXPRESSION LINK SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS, MONOCYTE-TO-MACROPHAGE DIFFERENTIATION, AND INTERFERON REGULATION
MicroRNAs (miRNAs) are small noncoding RNAs which post-transcriptionally regulate gene expression. The miR-17-92 cluster is well studied in cancer biology and cellular differentiation; its overexpression has been found to serve a major oncogenic role in the targeting and downregulation of tumor-suppressive pathways, such as PTEN or TGFß. Our previous work identified several members of the cluster – miR-18, miR-19a/b, miR-20a, and miR-92a – with significantly higher levels in monocytes from patients with active Systemic Juvenile Idiopathic Arthritis (SJIA). SJIA is a chronic inflammatory disease of childhood with features of autoinflammation, and innate immune cells including monocytes have important roles in disease pathogenesis. Children with SJIA are at risk for life-threatening complications including Macrophage Activation Syndrome (MAS), an episode of overwhelming inflammation characterized by macrophage proliferation and driven by IFNγ. Characterize the regulation of the miR-17-92 cluster, define key targets, and determine the cluster’s role in inflammation and SJIA. MiRNA levels were examined in THP-1 cells, as well as primary human monocytes isolated from healthy donors over the course of the monocyte to monocyte-derived macrophage (MDM) transition. MiR-17, miR-19a, and miR-20a were overexpressed via transfection in CD14+ monocytes for 2 days. Transcriptional profiles were performed using Ampliseq Transcriptome and the Ion Torrent S5 system and analyzed using AltAnalyze. Potential targets of the miR-17-92 cluster determined from sequencing analysis were then validated via dual-luciferase reporter assay. Neither blood monocytes nor fully differentiated THP-1 cells showed significant changes in miR-17-92 levels under standard polarization conditions, including M1, M2a, and M2b conditions, or IL-6 and IL-10 stimulation. The most sizable changes in miR-17-92 levels were found during monocyte to macrophage transition. Interestingly, primary monocytes showed increases in miR-17-92 levels within the first 48 hours of differentiation towards MDM, variable by miRNA and experiment, similar to that seen in SJIA monocytes. In contrast, both PMA-differentiated THP1 cells and fully differentiated MDMs showed decreased miR-17-92 compared to undifferentiated monocytic cells. MiR-17-92 was overexpressed in vitro in primary monocytes to model these early transition changes. Genome-wide transcriptional profiling showed an upregulation of genes involved in Type I and II Interferon pathways, including response to interferon-alpha (adjusted p=2.71x10-12) and interferon-gamma (adjusted p=7.81x10-9). Analysis of genes significantly downregulated by miR-17, miR-19a, or miR-20a identified several putative and previously validated miR-17-92 cluster targets, including ATG5, IFRD2, JAK1, PPARG, and PTPN2 which have interferon-regulatory functions. Dual-luciferase reporter assay experiments support that these genes are direct targets of miR-17, miR-19a, and/or miR-20a. MiR-17-92 cluster members demonstrate initial increase followed by subsequent decrease in expression during 2-week human monocyte to macrophage differentiation. Overexpression of miR-17-92 miRNAs upregulates Type I and II interferon pathway genes, and these miRNAs target multiple genes involved in regulating interferon signaling and/or inflammatory response. Taken together, miR-17-92 cluster overexpression in SJIA monocytes may suggest a more differentiated phenotype, and contribute to IFNγ sensitivity and risk for MAS. None declared
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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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