Detection and Prediction of Macrophage Activation Syndrome in Still's Disease.
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ABSTRACT:
SUBMITTER: Javaux C
PROVIDER: S-EPMC8745834 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Still's disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still's disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still's disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still's disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still's disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still's disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still's disease and macrophage activation syndrome.
| S-EPMC9705324 | biostudies-literature
Project description:BackgroundAdult-onset Still's disease (AOSD) is a systemic autoinflammatory disease characterized by innate immune system activation, with a high risk for macrophage activation syndrome (MAS). MAS development is associated with monocyte/macrophage activation and cytokine storm. Monocytes consist of three different subsets, classical monocytes (CMs, CD14brightCD16 -), intermediate monocytes (IMs, CD14brightCD16 +), and non-classical monocytes (NCMs, CD14dimCD16 +), each has distinct roles in inflammatory regulation. However, the frequencies and regulatory mechanism of monocyte subsets in AOSD patients have not been identified.MethodsWe performed flow cytometry, RNA sequencing, phagocytosis analysis, and enzyme-linked immunosorbent assay to evaluate monocyte subsets, cell functions, and potential biomarkers. The effect of neutrophil extracellular traps (NETs) on monocytes was determined by evaluating mRNA levels of DNA sensors, surface CD16 expression, and inflammasome pathway activation.ResultsHigher proportions of intermediate monocytes (IMs) were identified in active AOSD patients. IMs displayed higher expression of CD80, CD86, HLA-DR, and CD163 than CMs and NCMs. CD163 upregulation was noted on AOSD IMs, accompanied by increased phagocytic activity and elevated cytokine/chemokine production, including IL-1β, IL-6, CCL8, and CXCL10. The frequencies of IMs were correlated with disease activity and higher in AOSD patients with MAS (AOSD-MAS). CCL8 and CXCL10 were highly expressed in RNA sequencing of monocytes from AOSD-MAS patients and plasma CXCL10 level could serve as a potential biomarker for AOSD-MAS. Moreover, DNA-sensing pathway was activated in monocytes from AOSD-MAS patients. Stimulation with NETs derived from AOSD induced DNA sensor expression, the expansion of IMs, and inflammasome pathway activation. These effects can be abrogated by DNase I treatment.ConclusionsOur results demonstrated that the proportions of IMs were elevated in AOSD and associated with MAS. The DNA component in NETs from AOSD plays an important role in the formation of IMs, shedding new light for the therapeutic target.
| S-EPMC10734198 | biostudies-literature
Project description:BackgroundAdult-onset Still's disease (AOSD) is an autoinflammatory multi-systemic syndrome. Macrophage activation syndrome (MAS) is a potentially life-threatening complication of AOSD with a mortality rate of 10-20%. Especially viral infection is thought to be a common trigger for development of MAS. On the other hand, the occurrence of MAS following vaccinations is extremely rare and has been described in a few cases after measles or influenza vaccinations and more recently after ChAdOx1 nCoV-19 (COVID-19 viral vector vaccine, Oxford-AZ).Case presentationWe report the case of a twenty-year-old female with adult-onset Still's disease (AOSD), who developed a MAS six days after receiving her first COVID-19 vaccine dose of BNT162b2 (mRNA vaccine, BioNTech/Pfizer) with ferritin levels of 136,680 µg/l (ref.: 13-150 µg/l).ConclusionsTo the best of our knowledge, this is the first case report of development of MAS in a patient with preexisting AOSD after vaccination in general, and SARS-CoV-2 vaccination in particular. The new mRNA vaccines have generally shown a reassuring safety profile, but it has been shown that nucleic acids in general, including mRNA can act as pathogen-associated molecular patterns that activate toll-like receptors with extensive production of pro-inflammatory cytokines and further activation of immune cells. Proving an interferon 1 response in our patient directly after vaccination, we think that in this particular case the vaccination might have acted as trigger for the development of MAS. Even if it remains difficult to establish causality in the case of rare adverse events, especially in patients with autoimmune or autoinflammatory conditions, these complications are important to monitor and register, but do not at all diminish the overwhelming positive benefit-risk ratio of licensed COVID-19 vaccines.
| S-EPMC8712099 | biostudies-literature
Project description:We report a case of a young woman with adult-onset Still's disease presenting as macrophage-activation syndrome complicated by shock and respiratory failure during the third trimester of pregnancy.Case summaryA previously healthy 26-year-old woman at 35 weeks of gestation presented with 1 week of constitutional symptoms and was found to be febrile, tachycardic, and hypotensive. She delivered a healthy neonate by cesarean section. Following delivery, she had worsening hypotension and fevers despite fluid resuscitation and antibiotics, and developed progressive hypoxemia requiring up to 60% Fio2, with bilateral upper-lobe predominant opacities on chest CT. She also had laboratory derangements including anemia, thrombocytopenia, low fibrinogen, elevated ferritin, and abnormal liver chemistries. After extensive testing to exclude infections, hemolysis, and other pertinent disorders, the development of polyarthralgias and a characteristic rash fulfilled criteria for adult-onset Still's disease complicated by macrophage-activation syndrome. Her condition improved with immunosuppressive therapy.ConclusionTo our knowledge, this is the first report of new-onset adult-onset Still's disease during the third trimester of pregnancy, which presented as macrophage-activation syndrome. In the context of late pregnancy, macrophage-activation syndrome can mimic or raise concern for hemolysis, elevated liver enzymes, and low platelet syndrome and other peripartum disorders. Furthermore, the characteristic articular symptoms of adult-onset Still's disease may be mild and/or delayed, and pulmonary involvement with severe hypoxemia can occur. Clinicians should consider this diagnosis when evaluating a pregnant patient with unexplained fever and multiorgan dysfunction.
| S-EPMC8148416 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH), or termed macrophage activation syndrome (MAS) when associated with rheumatic disorders, is a frequently fatal complication of infections, rheumatic disorders, and hematopoietic malignancies. Clinically, HLH/MAS is a life-threatening condition that is usually diagnosed among febrile hospitalized patients (children and adults) who commonly present with unremitting fever and a shock-like multiorgan dysfunction scenario. Laboratory studies reveal pancytopenia, elevated liver enzymes, elevated markers of inflammation (ESR, CRP), hyperferritinemia, and features of coagulopathy. In about 60% of cases, excess hemophagocytosis (macrophages/histiocytes engulfing other hematopoietic cell types) is noted on biopsy specimens from the bone marrow, liver, lymph nodes, and other organs. HLH/MAS has been hypothesized to occur when a threshold level of inflammation has been achieved, and genetic and environmental risk factors are believed to contribute to the hyperinflammatory state. A broad variety of infections, from viruses to fungi to bacteria, have been identified as triggers of HLH/MAS, either in isolation or in addition to an underlying inflammatory disease state. Certain infections, particularly by members of the herpesvirus family, are the most notorious triggers of HLH/MAS. Treatment for infection-triggered MAS requires therapy for both the underlying infection and dampening of the hyperactive immune response.
| S-EPMC7123081 | biostudies-literature
Project description:IntroductionPatients with adult-onset Still's disease (AOSD) are at risk of developing macrophage activation syndrome (MAS), a life-threatening condition. Some cases of MAS have been reported following the use of biological agents, highlighting the need to identify contributing factors. This study aims to examine the characteristics of MAS in patients with AOSD treated with anakinra (ANA) or tocilizumab (TCZ).MethodsA systematic search was conducted across four online databases to identify studies reporting the incidence rates of MAS in patients with AOSD treated with ANA or TCZ. Meta-analysis was performed using a random-effects model and the generic inverse variance method to estimate the pooled incidence rates. The difference in incidence rates of MAS between TCZ and ANA was assessed. Additionally, we analyzed laboratory data and clinical features of AOSD cases at our institution, stratifying them into two groups: those who developed MAS after TCZ administration and those who did not.ResultsOf the 455 screened articles, we included five ANA and six TCZ studies. The pooled incidence rates of MAS were 1.50% (95% confidence interval [CI], 0-3.36) for ANA (345 patients) and 14.01% (95% CI 4.51-23.51) for TCZ (94 patients). MAS incidence was significantly higher in the TCZ group (P = 0.01). Among the 17 patients from our institution, the six patients who developed MAS had significantly higher white blood cell and neutrophil counts, as well as elevated levels of lactate dehydrogenase, C-reactive protein, and ferritin before TCZ induction (P < 0.05).ConclusionsIn patients with AOSD, the manifestation of MAS is influenced by multiple causative factors. Consequently, the administration of TCZ should be approached with caution, particularly in patients exhibiting elevated inflammatory markers.Trial registrationThis study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (Japan) as UMIN000049243.
| S-EPMC10654298 | biostudies-literature
Project description:BackgroundTo investigate the potential utility of quantitative parameters obtained by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the assessment of disease severity and the occurrence of macrophage activation syndrome (MAS) in adult-onset Still's disease (AOSD).MethodsFifty-seven patients with AOSD who underwent pre-treatment 18F-FDG PET/CT were recruited in this study and compared with 60 age- and sex-matched healthy controls. Clinical features and laboratory data were recorded. The systemic score was assessed to determine the disease severity. The maximal standardized uptake value (SUVmax), metabolic lesion volume (MLV), and total lesion glycolysis (TLG) were used to evaluate the involved organs and tissues that abnormally accumulated 18F-FDG. Multivariate analysis was performed to identify the PET/CT-derived risk factors contributing to the AOSD-related MAS, and their diagnostic efficiency was evaluated.ResultsHigh 18F-FDG accumulation was observed in the bone marrow (SUVmax median, 5.10), spleen (SUVmax median, 3.70), and lymph nodes (LNs, SUVmax median, 5.55). The SUVmax of the bone marrow (rho = 0.376, p = 0.004), SUVmax of the spleen (rho = 0.450, p < 0.001), TLGtotal of LNs (rho = 0.386, p = 0.017), and MLVtotal of LNs (rho = 0.391, p = 0.015) were correlated with the systemic score. The SUVmax of the spleen (p = 0.017), TLGtotal of LNs (p = 0.045), and MLVtotal of LNs (p = 0.012) were higher in patients with MAS than in those without MAS. A MLVtotal of LNs > 62.2 (OR 27.375, p = 0.042) was an independent predictive factor for MAS with a sensitivity of 80.0% and a specificity of 93.9%.ConclusionsThe glucose metabolic level of the spleen could be an effective and easy-to-use imaging indicator of disease severity, and MLVtotal of LNs > 62.2 was a strong predictor of MAS occurrence in patients with AOSD.
| S-EPMC8008587 | biostudies-literature
Project description:IntroductionAdult-onset still's disease (AOSD) is a rare systemic inflammatory disorder in which abnormalities in inflammatory cytokines production appear to play a pathophysiological role. Our previous work has reported increased expression of macrophage migration inhibitory factor (MIF) and revealed its correlation with disease severity and activity in AOSD. A -173 G/C single nucleotide polymorphism (SNP) (rs755622) and a -794 CATT₅₋₈ repeat (rs5844572) in the MIF promoter have been reported. In this study, we sought to explore the relationship between functional MIF promoter polymorphisms and MIF expression in AOSD.Methods100 patients and 200 controls were recruited in the study. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the -173 G/C SNP (rs755622) and PCR-based size discrimination assay was applied to detect the -794 CATT₅₋₈ repeat (rs5844572) in the MIF promoter. Plasma MIF levels were measured by ELISA. MIF mRNA levels were quantified by real-time reverse transcription (RT)-PCR. Bisulfate genomic sequencing was employed to evaluate DNA methylation status within the MIF promoter.ResultsWe identified that the frequencies of MIF -794 CATT₅ (P = 0.001) allele and the expression of MIF (P <0.001) were increased in patients compared to healthy controls. Plasma levels of MIF in patients with CC genotype were higher than those of patients with GC or GG genotypes (P = 0.05). In patients with established AOSD, a higher frequency of -794 CATT₇ containing MIF genotypes was observed in those with liver dysfunction (P = 0.009). Haplotype analysis revealed a higher representation of the MIF haplotype defined by -173*C/-794 CATT₅ (C5) in AOSD patients (P = 0.001).ConclusionFunctional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSD and may contribute to disease susceptibility or clinical presentation of AOSD.
| S-EPMC4060242 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are 2 similar diseases characterized by a cytokine storm, overwhelming inflammation, multiorgan dysfunction, and death. Animal models of HLH suggest that disease is driven by IFN-? produced by CD8? lymphocytes stimulated by persistent antigen exposure. In these models and patients with "primary" HLH, the antigen persists due to genetic defects, resulting in ineffective cytotoxic responses by CD8? T cells and poor pathogen clearance. However, infectious triggers are often not identified in patients with MAS, and some patients with HLH or MAS lack defects in cytotoxic T cell killing. Herein, we show that repeated stimulation of TLR9 produced an HLH/MAS-like syndrome on a normal genetic background, without exogenous antigen. Like previous HLH models, TLR9-induced MAS was IFN-? dependent; however, unlike other models, disease did not require lymphocytes. We further showed that IL-10 played a protective role in this model and that blocking IL-10 signaling led to the development of hemophagocytosis. IL-10 may therefore be an important target for the development of effective therapeutics for MAS. Our data provide insight into MAS-like syndromes in patients with inflammatory diseases in which there is chronic innate immune activation but no genetic defects in cytotoxic cell function.
| S-EPMC3104738 | biostudies-literature
Project description:Adult-onset Still’s disease (AOSD) is a rare autoinflammatory disease, characterized by fever, rash, arthritis and other systemic inflammatory manifestations like hepatosplenomegaly and serositis. One of the most serious complications AOSD is macrophage activation syndrome (MAS), a life-threatening condition caused by excessive activation of immune system and a cytokine storm. Clinical features of MAS include continuous high fever, hepatosplenomegaly, liver dysfunction, lymphadenopathy, hyperferritinemia, and hemophagocytosis. The prevalence of MAS in AOSD patients is estimated to be between 10–19%, but the mortality rate of AOSD-associated MAS is approximately 10–20%. The precise mechanism by which AOSD develops to MAS remains unclear. There is an unmet need to investigate the pathogenesis of MAS in AOSD in order to identify novel biomarkers and therapeutic targets to improve disease prognosis.
2023-12-22 | GSE247993 | GEO