Active Adult-onset Still's Disease Research Articles

Serum Mac-2 binding protein glycosylation isomer and galectin-3 levels in adult-onset Still's disease and their association with cytokines.

Autoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still's disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD. We recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks. Significant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p <0.001). There were significant positive correlations between serum Gal-3 levels and AOSD disease activity score (Pouchot score, r=0.66, p <0.001) and serum ferritin levels. However, no significant correlations were observed between serum M2BPGi levels and AOSD disease activity scores (Pouchot score, r = 0.32, p = 0.06) or serum ferritin levels. Furthermore, significant correlations were observed between the serum levels of Gal-3 and various inflammatory cytokines, including interleukin-18, in patients with AOSD. Immunosuppressive treatment in patients with AOSD significantly reduced serum Gal-3 and M2BPGi levels (p = 0.03 and 0.004, respectively). Although both Gal-3 and M2BPGi were elevated in patients with AOSD, only Gal-3 was a useful biomarker for predicting disease activity in AOSD. Our findings suggest that circulating Gal-3 reflects the inflammatory component of AOSD, which corresponds to proinflammatory cytokine induction through inflammasome activation cascades.

The landscape of innate and adaptive immune cell subsets in patients with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder. The understanding of the changes in adaptive immune cells and the crosstalk between innate and adaptive immune systems in AOSD is limited. This study aimed to examine the peripheral immune cell composition and inflammatory protein levels in AOSD patients. Twenty-nine active AOSD patients were enrolled. Flow cytometry was used to analyze the cell populations in peripheral blood. Antibody chips were utilized to detect the protein expression profile in serum. In active AOSD patients, there was an increase in the percentage of classical and non-classical monocytes among peripheral blood mononuclear cells. The proportion of natural killer (NK) cells decreased, with an increase in CD56dim NK1 cells and a decrease in CD56bright NK2 cells compared with healthy controls (HC). The percentage of naïve central memory T cells was decreased, while the percentage of effector and effector memory T cells was increased among adaptive lymphocytes. The proportion of naïve B and memory B cells was decreased, while plasma cells were increased in AOSD patients, indicating activation of the adaptive immune system. Additionally, the serum levels of 40 proteins were elevated in AOSD patients, primarily involved in cytokine-cytokine receptor interaction, inflammatory response, and regulation of MAPK cascade. Our findings showed the activation of the innate and adaptive immune system in AOSD. The protein-protein interaction analysis suggested potential communication between innate and adaptive cell subsets. These findings provide new insights into the pathogenesis of the disease and the development of targeted therapies.

Elevated monocyte distribution width in patients with active adult-onset Still's disease: a novel activity indicator.

Monocyte distribution width (MDW) correlates with volume modifications of circulating monocytes upon activation. Given the crucial role of monocyte activation in the pathogenesis of adult-onset Still's disease (AOSD), we aimed to examine the associations between MDW and disease activity or inflammatory parameters in this disease. In 58 AOSD patients and 95 other patients with coronavirus disease 2019 (COVID-19) as disease control, MDW and complete blood count were determined using a UniCel DxH800 analyser. C-reactive protein (CRP) levels were measured by nephelometry, and ferritin levels by chemiluminescent immunoassay. AOSD activity was assessed using a modified Pouchot score. MDW was significantly higher in active AOSD patients (median 28.3, interquartile range [IQR] 23.3-32.1) compared with inactive AOSD (19.2, IQR 18.0-20.6, p<0.001) or non-severe COVID-19 patients (23.2, IQR 21.0-25.2, p<0.01). MDW was positively correlated with AOSD activity scores, CRP, and ferritin levels (all p<0.001). Longitudinal follow-up evaluation revealed that median MDW significantly declined (28.3 versus 18.5, p<0.001) along with disease activity, paralleling a decrease in CRP and ferritin levels. Severe COVID-19 and sepsis patients had elevated MDW, which were not different from active AOSD patients. Multivariate analysis revealed MDW as a significant predictor of active AOSD, and MDW threshold at 21.7 could predict an active status with a high sensitivity of 91.3% and specificity of 94.3%. Elevated MDW and its positive correlation with inflammatory parameters in AOSD patients indicate MDW as a novel activity indicator, with a high MDW value above 21.7 linked to a high probability of active AOSD.

Activation mechanisms of monocytes/macrophages in adult-onset Still disease.

Adult onset Still disease (AOSD) is a systemic inflammatory disorder characterized by skin rash, spiking fever, arthritis, sore throat, lymphadenopathy, and hepatosplenomegaly. Although the etiology of this disease has not been fully clarified, both innate and acquired immune responses could contribute to its pathogenesis. Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity, as well as hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD. In innate immunity, activation of monocytes/macrophages might play central roles in the development of AOSD and macrophage activation syndrome (MAS), a severe life-threating complication of AOSD. Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA. These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1β and pro-IL-18 into mature forms. Thereafter, IL-1β and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD. We identified placenta-specific 8 (PLAC8) as a specifically increased molecule in monocytes of active AOSD, which correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Interestingly, PLAC8 could suppress the synthesis of pro-IL-1β and pro-IL-18 via enhanced autophagy; thus, PLAC8 seems to be a regulatory molecule in AOSD. These findings for the activation mechanisms of monocytes/macrophages could shed light on the pathogenesis and development of a novel therapeutic strategy for AOSD.

Adult-onset Still's disease: A disease at the crossroad of innate immunity and autoimmunity.

Adult-onset Still’s disease (AOSD) is a rare disease affecting multiple systems and organs with unknown etiology, and the clinical symptoms are usually described as spiking fever, arthritis, evanescent salmon-pink eruptions, lymphadenopathy, splenomegaly, and other manifestations. The laboratory indicators are not specific, often presenting as increased leukocyte counts and neutrophil percentage, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), hyperferritinemia, and increased inflammatory factors. ANA, ENA, and RF are negative. According to those unspecific clinical presentations and laboratory findings, infection, tumor, connective tissue disease, and other diseases must be ruled out before diagnosis. The diagnosis of AOSD is a great challenge for clinicians. The mechanism of AOSD pathogenesis is complicated and still being studied. There is a new opinion that atypical persistent skin eruptions (APSEs) with specific histological manifestations are unique for AOSD, and APSEs might be on a spectrum with classical evanescent eruptions. Studies on APSEs showed that IL-1β and IFN-γ are strongly correlated with the pathogenesis of necrosis keratinocytes in APSEs. IL-1β is strongly involved in inflammatory disease when it is abnormal, and plays an important role in the pathogenesis of neutrophil dermatosis. In the early stage of AOSD, skin lesions appear to be evanescent urticaria-like eruptions accompanied by fever, and only neutrophils infiltrate around the blood vessels in the dermis pathologically. As the course of the disease progresses, IL-1β is gradually released. Through the stimulation of other inflammatory factors and the influence of unknown factors, IL-1β gradually infiltrates into the stratum corneum and finally accumulates around the necrotic keratinocytes of the stratum corneum. However, the detailed mechanism is still unknown. IFN-γ could play a pro-inflammatory or regulatory role in some disorders. IL-1β can enhance the expression of IFN-γ, and IFN-γ can cause keratinocyte apoptosis by activating the autocrine of caspase. Also, several pieces of evidence indicate that adaptive immunity is also involved in the pathogenesis of AOSD. Increased α-soluble receptors of IL-2 may suggest T-cell activation and proliferation in AOSD patients. Increased IL-4- and IFN-γ-producing T cells were found in active AOSD and related to disease severity. Frequencies of Treg cells in AOSD were significantly lower and were inversely correlated with disease severity. According to these, more and more researchers have reached a consensus that AOSD is a disease at the crossroads of innate immunity and autoimmunity. In this review, we will provide a comprehensive insight into AOSD, describing research progress and the immunological mechanism contribution to the disease. In the meantime, different treatment options and the efficacy and safety of various biologic agents are also discussed. A further understanding of AOSD requires closer cooperation among doctors from different departments, and this review will provide a new idea for diagnosis and therapeutic options.

Serum Interleukin-18 Provides a Clue to the Diagnosis of Adult-Onset Still's Disease: Findings from 6 Japanese Patients with Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder accompanied by skin eruption. However, typical skin eruptions, such as evanescent, salmon-pink erythema, are not specific to AOSD and dermatologists often face difficulty in diagnosing AOSD. In this study, we examined serum IL-18 levels as well as IL-6, ferritin and C-reactive protein in 6 Japanese patients with AOSD. Serum levels of IL-6 and IL-18 were evaluated in the acute phase and at the time of remission. Serum levels of IL-6 were analyzed using a commercial chemiluminescent enzyme immunoassay (CLEIA; SRL, Tokyo, Japan). Serum IL-18 levels were measured using a commercial ELISA kit (Medical & Biological Laboratories Co., LTD. Nagoya, Japan). In active AOSD, serum ferritin levels and CRP levels were above normal range in 6 patients. In remission, serum ferritin levels of 3 patients were slightly above the normal range, while CRP serum levels of 6 patients were all normalized. Serum IL-18 levels were markedly elevated in 5 cases during the acute phase. In remission, serum IL-18 levels remained at higher values than the normal range in 5 cases. Serum IL-6 levels were also highly elevated in 5 patients in active AOSD and became normalized in remission except in case 2. High levels of serum IL-18 will be a clue to the diagnosis of AOSD. CRP is also useful biomarker for monitoring disease activity compared with IL-6 and IL-18.

Enhanced type I interferon signature induces neutrophil extracellular traps enriched in mitochondrial DNA in adult-onset Still's disease

Adult-onset Still's disease (AOSD) is a rare but clinically well-known auto-inflammatory disorder. Cytokine storm, the hallmark of AOSD, is mediated by neutrophil hyperactivation and enhanced neutrophil extracellular trap (NET) formation. Type I interferons (IFNs), having a primary role in the initiation of proinflammation responses, can induce subsequent inflammatory cytokine production. However, the role of type I IFNs in AOSD is unclear. Indeed, high levels of IFN-α and IFN-β expression are presented by AOSD patients. In this investigation, hierarchical unsupervised clustering was performed on IFN-α and IFN-β data to identify a cluster of AOSD patients who had a serious condition. Neutrophils from treatment-naïve active AOSD patients showed very strong enrichment in their IFN-α response, as shown by RNA-seq and confirmed by the IFN score. Whether IFN-α stimulates NET formation was also tested. IFN-α had the ability to form NETs that contained oxidized mitochondrial DNA (ox-mtDNA). Moreover, the JAK inhibitor could be used to dampen type I IFN-induced NET formation and eventually control ox-mtDNA release. Our results demonstrated the important roles of type I IFNs in the pathogenesis of AOSD through their promotion of NET formation, as characterized by the enhanced level of ox-mtDNA. The findings open up new avenues of research into therapeutic approaches for AOSD.

The performance of the diagnostic scoring system or criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis for adult-onset Still's disease. A multicentre case-control study in China.

To evaluate the performance of the diagnostic scoring system/criteria for macrophage activation syndrome (MAS) used in systemic juvenile idiopathic arthritis (sJIA) for adult-onset Still's disease (AOSD). This retrospective case-control study included AOSD patients with and without MAS from six hospitals in China. The cut-off values that best discriminated MAS from active AOSD were determined by receiver operating characteristic (ROC) curve analysis. The performance of the present diagnostic scoring system/criteria for sJIA-MAS was evaluated in AOSD-associated MAS. The optimal critical value of the ROC curve replaces the relevant indicators of the existing scoring system and different models were tested for sensitivity/specificity. A total of 56 AOSD-associated MAS patients (AOSD-MAS) and 112 AOSD patients without MAS matched with age and sex treated at six centres between 2007 and 2017 were enrolled. The 2016 MAS in sJIA classification criteria had an overall sensitivity of 100.0% and specificity of 80.4% for classifying AOSD-MAS. Excluding hypertriglyceridemia and substituting some other criteria with newly obtained cut-off values could increase specificity. An MS score ≥-2.1 yielded a sensitivity of 95.2% and a specificity of 76.6% in classifying AOSD-MAS. ROC curve analysis revealed that a score of -1.74 could best discriminate AOSD-MAS from AOSD without MAS. An MS score ≥-1.74 yielded a sensitivity of 93.5% and a specificity of 92.6% in diagnosing AOSD-MAS (AUC=0.96, 95%CI: 0.93-0.99, p<0.0001). The diagnostic tool for MAS in sJIA with modification appears to apply to AOSD-MAS.

Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in AOSD. Serum samples were obtained from 44 patients with active AOSD or 50 patients with rheumatoid arthritis (RA), 20 patients with systemic lupus erythematosus (SLE), and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay. Results were compared among AOSD patients, RA patients, SLE patients and HCs. Results were also analyzed according to the clinical features of AOSD. Serum CIRP levels were significantly higher in AOSD patients compared with RA patients (median: 9.6 ng/mL, IQR [5.7-14.4] versus 3.2 ng/mL, IQR [1.9-3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4-4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and AOSD disease activity score (Pouchot's score r = 0.45, p = 0.003) as well as between AOSD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among AOSD patients with three different disease phenotypes. These results suggest that CIRP may play a significant role in the pathophysiology of AOSD and could be a potential biomarker for monitoring the disease activity of AOSD.

Interleukin-18 Is a Potential Biomarker to Discriminate Active Adult-Onset Still's Disease From COVID-19.

BackgroundHyperinflammation with dysregulated production of galectins and cytokines may develop in COVID-19 or adult-onset Still’s disease (AOSD). Given the similar clinical features in both diseases, it is necessary to identify biomarkers that can differentiate COVID-19 from AOSD. However, the related data remain scarce currently.MethodsIn this cross-sectional study, plasma levels of galectin-3, galectin-9, and soluble TIM-3 (sTIM-3) were determined by ELISA in 55 COVID-19 patients (31 non-severe and 24 severe), 23 active AOSD patients, and 31 healthy controls (HC). The seropositivity for SARS-CoV-2 was examined using an immunochromatographic assay, and cytokine profiles were determined with the MULTIPLEX platform.ResultsSignificantly higher levels of galectin-3, galectin-9, IL-1β, IL-1Ra, IL-10, IFN-α2, IL-6, IL-18, and TNF-α were observed in severe COVID-19 and active AOSD patients compared with HC (all p<0.001). AOSD, but not COVID-19, showed significantly higher IFN-γ and IL-17A compared with HC (both p<0.01). Moreover, active AOSD patients had 68-fold higher IL-18 levels and 5-fold higher ferritin levels than severe COVID-19 patients (both p<0.001). IL-18 levels at the cut-off value 190.5pg/mL had the highest discriminative power for active AOSD and severe COVID-19, with AUC 0.948, sensitivity 91.3%, specificity 95.8%, and accuracy of 91.5% (p<0.005). Multivariate regression analysis revealed IL-18 as a significant predictor of active AOSD (p<0.05).ConclusionActive AOSD patients share features of hyperinflammation and cytokine storm with severe COVID-19 patients but possess a distinct cytokine profile, including elevated IL-18, IL-6, IFN-γ, and IL-17A. IL-18 is a potential discriminator between AOSD and COVID-19 and may significantly predict active AOSD.

Characteristics and Clinical Value of 18F-FDG PET/CT in the Management of Adult-Onset Still's Disease: 35 Cases.

While the diagnosis of adult-onset Still’s disease (AOSD) involves the exclusion of differential diagnoses, the characteristics and value of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography coupled with CT (PET/CT) in the management of AOSD remain poorly known. Our retrospective study included patients from four centers, fulfilling Yamaguchi or Fautrel criteria, who underwent a PET/CT during an active AOSD. Thirty-five patients were included. At the time of PET/CT, the Yamaguchi criteria were met in 23 of 29 evaluable cases. PET/CT showed bone marrow (74.3%), lymph node (74.3%), and splenic (48.6%) FDG uptake. Despite arthralgia or arthritis in most patients, joints were rarely the sites of 18F-FDG accumulation. The spatial distribution of 18F-FDG uptake was nonspecific, and its intensity could be similar to malignant disease. Lymph node or bone marrow biopsy was performed after PET/CT in 20 patients (57.1%). The intensity of bone marrow; splenic and lymph node hypermetabolism appeared to be correlated with disease activity. Abnormal PET/CT in the cervical lymph nodes and age ≥ 60 years seemed to be predictive factors for monocyclic evolution. The clinical value of PET/CT is not in direct diagnosis; but as an aid in excluding differential diagnoses by searching for their scintigraphic features and guiding biopsy.

Serum Heparin-Binding Protein as a Potential Biomarker to Distinguish Adult-Onset Still’s Disease From Sepsis

Adult-onset Still’s disease (AOSD) is a systemic, multifactorial, autoinflammatory disease for which the etiopathogenesis is not well understood. Given the similarities in clinical and laboratory features between this disease and sepsis, and the differences in treatment strategies for these two diseases, specific diagnostic markers are crucial for the correct diagnosis and management of AOSD. Previous studies have shown plasma heparin-binding protein (HBP) is a promising potential biomarker for AOSD; thus, this study aimed to detect serum HBP levels in patients with AOSD or sepsis to assess its potential as a biomarker for differential diagnosis. We found that serum HBP levels were significantly higher in patients with active AOSD than that in those with inactive AOSD. Patients with sepsis had higher serum HBP levels compared with those who had active or inactive AOSD. We calculated the area under the receiver operating characteristic (ROC) curve to assess whether HBP could be used to differentiate active from inactive AOSD; this was 0.811 with sensitivity 0.650, specificity 0.811, and cutoff HBP value of 35.59 ng/ml. The area under the ROC curve for HBP as a biomarker to differentiate AOSD from sepsis was 0.653, with sensitivity 0.759, and specificity 0.552, and cutoff HBP value of 65.1 ng/ml. Taken together, the results of our study suggest that serum HBP could be a useful diagnostic biomarker to evaluate disease activity in patients with AOSD, and to differentiate AOSD from sepsis.

Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease.

Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA. Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time. Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo. Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.

Cytokine Storm in Coronavirus Disease 2019 and Adult-Onset Still’s Disease: Similarities and Differences

The catastrophic outbreak of coronavirus disease 2019 (COVID-19) is currently a public emergency. Adult-onset Still’s disease (AOSD) is an autoinflammatory disease characterized by life-threatening complications. Systemic hyperinflammation and cytokine storm play a critical role in the pathogenesis of both COVID-19 and AOSD. We aimed to compare the similarities and differences focusing on ferritin and cytokine levels between severe COVID-19 and active AOSD. A literature search was performed using the databases PubMed, EMBASE, and Web of Science to collect the levels of cytokine including IL-1β, IL-6, IL-18, TNF-α, IL-10, and ferritin in severe COVID-19 patients. After extracting available data of indicators of interest, we acquired these statistics with a single-arm meta-analysis. Furthermore, a comparison was conducted between 52 patients with active AOSD in our center and severe COVID-19 patients from databases. The levels of IL-6 and IL-10 were higher in severe COVID-19 compared with those in active AOSD. There were no significant differences on the cytokine of IL-1β and TNF-α. Fold changes of IL-18 were defined as the mean expression level ratio of severe COVID-19 to healthy controls in the COVID-19 study and active AOSD to healthy controls in our study, individually. Although the fold change of IL-18 in patients with AOSD was significantly higher than patients with severe COVID-19 (fold change: 594.00 vs 2.17), there was no statistical comparability. In addition, the level of ferritin was higher in active AOSD in comparison with severe COVID-19. Our findings suggest that severe COVID-19 and active AOSD have differences in cytokine panel and ferritin level, indicating the pathogenic role of ferritin in overwhelming inflammation. And it paves the way to make efficacy therapeutic strategy targeting the hyperinflammatory process in COVID-19 according to AOSD management, especially in severe COVID-19.

Derivation and Validation of Adult Still Activity Score (SAS)

Background/Aim: Adult-onset Still’s disease (AOSD) is a multi-systemic, autoinflammatory disorder. Several activity scores have been proposed but none of them have been adopted universally. Our aim was to create a clinician-friendly activity scoring system by using simple clinical and laboratory parameters. Methods: AODS patients according to Yamaguchi criteria were included in this cross-sectional, multi-center study. Derivation and validation cohorts were constituted. Demographic, clinical and laboratory evaluation at study visit; patients’, and physicians’ global assessments of disease activity (both VAS/ Likert scale) were recorded. To develop the score; ordinal logistic regression model was used to determine independent predictors of patient’ global assessments of disease activity. Clinically and statistically significant variables were weighted according to regression coefficients. Then, performance of the score was tested on the validation cohort. Results: Total of 197 consecutive AOSD patient (125 in derivation, 72 in validation cohorts) were included. Final Still Activity Score was fever (2 points), arthralgia (2 points, plus 1 point if arthritis was present in ≥2 joints), neutrophilia≥65% (1 point) and ferritin≥350 ng/mL (1 point) (maximum of 7 points). The SAS yielded an AUC value of 0.98(0.96-1.00) in the derivation cohort and 0.91(95%CI:0.85-0.98) in the validation cohort to discriminate high AOSD activity from moderate-inactive AOSD. Correlation of SAS with PtGA was 83% for the derivation cohort and 76% for the validation cohort. Conclusions: SAS has shown a good test performance to distinguish active AOSD patients from the others. SAS may be a useful method for evaluating disease activity of AOSD patients in daily practice. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: The present study was conducted in compliance with the Helsinki Declaration and was approved by the Local Ethics Committee of Hacettepe University (GO- 20/824). A written informed consent form was completed by all participants.

The neutrophil-to-lymphocyte ratio in complete blood cell count may be an available marker for active adult-onset Still's disease

In clinical practice, acute-phase protein measurements during inflammation are usually used to monitor the activity and severity of adult-onset Still's disease (AOSD).Objective: to study the possibility of using the neutrophil-to-lymphocyte ratio (NLR) in complete blood cell count as a marker for the activity and severity of AOSD in clinical practice.Patients and methods. The investigation enrolled 48 patients (29 females and 19 males; mean age, 32.8±12.5 years) with active AOSD, who met the criteria devised by M. Yamaguchi et al. Along with standard clinical and laboratory parameters and systemic scores, NLR was calculated in complete blood cell count.Results and discussion. There was a statistically significant correlation of NLR with the level of CRP (r=0.532), ferritin (r=0.43), ESR (r=0.40), and the systemic score reflecting the severity of the disease (r=0.449), which allows NLR to be regarded as a tool that is convenient to assess the activity and severity of AOSD in clinical practice.Conclusion. The findings have shown the good sensitivity and specificity of NLR, which indicates the possibility of using the latter as an available marker for assessing the activity and severity of AOSD in clinical practice.

Elevated Granulocyte Colony-stimulating Factor Levels in Patients With Active Phase of Adult-onset Still Disease.

Neutrophilia is a hallmark of adult-onset Still disease (AOSD). We aimed to investigate the levels of granulocyte colony-stimulating factor (G-CSF), an essential regulator of neutrophil production and function, in the pathogenesis of AOSD. Sera were collected from 70 patients with AOSD and 20 healthy controls (HCs). The levels of G-CSF were determined by ELISA. Low-density granulocytes (LDGs) were quantified by flow cytometry. Correlations between G-CSF levels and disease activity, laboratory variables, and LDG levels in patients with AOSD were analyzed by Spearman correlation test. Patients with active AOSD presented significantly higher levels of G-CSF compared to inactive AOSD patients (P < 0.001) and HCs (P < 0.0001). The G-CSF levels were significantly decreased after active AOSD patients achieved disease remission (P = 0.0015). The G-CSF levels were significantly correlated with C-reactive protein, erythrocyte sedimentation rate, ferritin, and systemic score in AOSD (P < 0.0001). Significant correlations between the levels of G-CSF and circulating neutrophils (P < 0.0001), neutrophil-to-lymphocyte ratio (P < 0.0001), percentages of LDGs in the peripheral blood mononuclear cells (P = 0.004), as well as absolute numbers of circulating LDGs (P = 0.018) were identified. Patients with fever, evanescent rash, sore throat, arthralgia, myalgia, lymphadenopathy, or hepatomegaly/elevated liver enzymes displayed significantly higher levels of G-CSF compared to patients without these manifestations (P < 0.05). Our findings indicate that G-CSF is implicated in the pathogenesis of AOSD, and targeting G-CSF may have therapeutic potential for AOSD. In addition, introducing circulating G-CSF levels into the clinical assessment system may help to monitor disease activity.

Successful treatment of interstitial pneumonitis with anakinra in a patient with adult-onset Still’s disease

A 29-year-old African woman with active adult-onset Still’s disease (AOSD) that developed at the end of 2018 presented to our hospital in September 2019 with pleuritic right-sided pain and respiratory...

Neutrophil-derived lipocalin-2 in adult-onset Still's disease: a novel biomarker of disease activity and liver damage.

ObjectiveLiver damage is a common manifestation and can be life-threatening in adult-onset Still’s disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD.MethodsTranscriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed.ResultsLCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694.ConclusionOur results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.

Elevated circulating pro-inflammatory low-density granulocytes in adult-onset Still's disease.

Neutrophilia is a hallmark of adult-onset Still's disease (AOSD). This study aimed to investigate the role of a distinct subset of granulocytes, the low-density granulocytes (LDGs) in the pathogenesis of AOSD. A total of 56 patients with AOSD were included in the study. LDGs were quantified by flow cytometry. Correlations between LDGs with disease activity and laboratory parameters were determined by Spearman's nonparametric test. The cellular sources of the pro-inflammatory cytokines in AOSD were determined by intracellular staining. Active AOSD patients displayed significantly higher levels of LDGs compared with inactive AOSD patients and healthy controls (HCs) (P<0.001). Circulating LDGs were significantly correlated with CRP, ESR and the modified Pouchot score in patients with AOSD (P<0.01). The levels of LDGs were significantly decreased after the active AOSD patients achieved disease remission (P=0.0391). CD14+ monocytes constituted over 90% IL-1β+ peripheral blood mononuclear cells (PBMCs) and over 80% TNF-α+ PBMCs in both active AOSD patients and HCs, respectively. In active AOSD, CD14+ monocytes accounted for 24.6% to 75.0% of IL-6+ PBMCs, while LDGs comprised 22.8% to 72.2% of IL-6+ PBMCs. In contrast, over 90% IL-6+ PBMCs were CD14+ monocytes in HCs. A significant correlation was identified between the levels of LDGs and serum IL-6 levels in AOSD (P<0.0001). Active AOSD is associated with elevated levels of a pro-inflammatory subset of neutrophils, the LDGs that produce IL-6. Our data highlight an unappreciated role of LDGs in the aberrant innate immune responses in AOSD.