Delay in the Diagnosis of Adult-Onset Still's Disease.
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ABSTRACT:
SUBMITTER: Pak S
PROVIDER: S-EPMC5501706 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:Adult-onset Still's disease (AOSD) is a systemic, multigenic autoinflammatory disease, and the diagnosis of AOSD must rule out neoplasms, infections, and other autoimmune diseases. Development of a rapid and efficient but non-invasive diagnosis method is urgently needed for improving AOSD therapy. In this study, we first performed a urinary proteomic study using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis in patients with AOSD and healthy control (HC) subjects. The urinary proteins were enriched in pathways of the innate immune system and neutrophil degranulation, and we identified that the α-1-acid glycoprotein 1 (LRG1), orosomucoid 1 (ORM1), and ORM2 proteins were highly expressed in patients with AOSD. The elevated urine levels of LRG1, ORM1, and ORM2 were further validated by enzyme-linked immunosorbent assay in active patients with AOSD, disease controls, and HC subjects. Receiver operating characteristic curves showed that the areas under the curve of LRG1, ORM1, and ORM2 were 0.700, 0.837, and 0.736, respectively (all p < 0.05). Furthermore, we found that the urine levels of LRG1, ORM1, and ORM2 were positively correlated with the systemic score and erythrocyte sedimentation rate and that the urine levels of LRG1 were positively correlated with interleukin 1β (IL-1β), IL-6, and IL-18 levels, whereas the urine levels of ORM1 were positively correlated with the IL-1β level. Together, our study identified novel urinary markers for non-invasive and simple screening of AOSD.
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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. Neutrophil activation is the hallmark of AOSD. Here we aimed to identify candidate biomarker and to validate its association with clinical manifestations in AOSD. Transcriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Using cut-offs of >2.0 fold change with p<0.05, we identified 864 DEGs in neutrophils from patients with active AOSD compared to healthy donors, including 442 and 422 upregulated and downregulated genes in active AOSD, respectively. By gene ontology (GO) analysis, we identified several strongly enriched terms of biological process. The most significantly indicated GO term was neutrophil degranulation.
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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.
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Project description:Previous studies have revealed that several micro-organisms, especially DNA viruses, have been associated with adult-onset Still's disease (AOSD). However, there are no studies on the relationship between the presence of viral infections in AOSD patients with disease occurrence and reactivation. In the present study, we aimed to investigate the presence of antibodies against virus, virus DNA load and nucleic acid sensors in AOSD patients. Anti-viral antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in plasma samples from 100 AOSD patients and 70 healthy controls (HCs). The copy number of cytomegalovirus (CMV) DNA in 100 AOSD patients was detected by PCR. The expression levels of nucleic acid sensors interferon gamma-inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) in peripheral blood mononuclear cell (PBMC) and skin from AOSD patients and HCs were analyzed by PCR and immunohistochemistry. The levels of antibodies against CMV were significantly higher in AOSD patients compared to HCs. Moreover, the level of anti-CMV IgM antibody was significantly increased in patients with fever, sore throat, arthralgia and rash. CMV DNA was found in plasma of AOSD patients with disease new-onset and relapse. Furthermore, the copy number of CMV DNA significantly increased in patients with fever, sore throat, arthralgia and rash. And the significant associations of the CMV DNA level with the levels of leukocytes, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were observed. Moreover, we found an upregulation of cytoplasmic DNA-sensing receptor IFI16 and AIM2 in PBMC and skin from AOSD patients. In conclusion, our results showed that CMV infection may play a role in the initiation or amplification of inflammatory responses in AOSD.
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Project description:Interleukin 1? (IL-1?) is emerging as a master mediator of adult onset Still's disease (AOSD) pathogenesis. This pleiotropic cytokine, whose expression is under the control of the inflammasome pathway, has a wide type of effects. As a key mediator of innate immunity is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations. The study of proinflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1?, these levels being highly correlated with disease activity and severity. These experimental evidences and the analogy with other autoinflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1? as a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases. Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNF? failed to control symptoms. While a growing number of evidences supports the utilisation of anakinra in AOSD, a new generation of anti-IL1? antagonists is developing. Canakinumab and rilonacept, thanks to their higher affinity and longer half-life, could improve the management of this invalidating disease.
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Project description:Adult-onset Still's disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still's disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.
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