Abstract
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.
Highlights
Adult-onset Still’s disease (AOSD) is a systemic, multigenic autoinflammatory disease characterized by cardinal manifestations of fever, arthritis and/or arthralgia, skin rash, sore throat, leukocytosis, and excessive neutrophil proportion, in combination with other symptoms, such as myalgia, pericarditis, pleuritis, and elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin levels [1,2,3]
We explored the urinary levels of LRG1, orosomucoid 1 (ORM1), and ORM2 in patients with AOSD, rheumatoid arthritis (RA), neoplasms, and infections and healthy control (HC) subjects by enzyme-linked immunosorbent assay (ELISA) and determined the correlation between the urinary levels of LRG1, ORM1, and ORM2 and clinical symptoms of AOSD
We further explored the urine proteomics of AOSD by isobaric tags for relative and absolute quantification (iTRAQ)-labeling combined with LCMS/MS analysis
Summary
Adult-onset Still’s disease (AOSD) is a systemic, multigenic autoinflammatory disease characterized by cardinal manifestations of fever, arthritis and/or arthralgia, skin rash, sore throat, leukocytosis, and excessive neutrophil proportion, in combination with other symptoms, such as myalgia, pericarditis, pleuritis, and elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin levels [1,2,3]. Macrophage and neutrophil activation–associated inflammatory cytokine storms play a crucial role in the disease progression of AOSD [1,2,3]. Pathogen-associated molecular patterns or dangerassociated molecular patterns trigger inflammasome activation and the production of interleukin 1β (IL-1β) and IL-18, further improving the expression of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and IL-6 and the antiinflammatory cytokines IL-10 and IL-37 [1, 6, 7]. A markedly high frequency of elevated serum molecules such as alarmins (S100A8/A9 and S100A12), chemokines (C-X-C motif chemokine ligand 9, 10, and 11), and microRNAs, which correlate with disease activity, was noticed in patients with AOSD [8,9,10,11,12]
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