Adult-onset Still's Disease Patients Research Articles

Adult-onset Still’s disease: analysis of a monocentric cohort of patients

Objective Adult-onset Still’s disease (AOSD) is a multigenic autoinflammatory disease with a severe systemic involvement. Because of the rarity of the disease, most published cohorts are multicentric. The aim of this report is to describe a monocentric cohort of AOSD patients, reporting clinical features and response to therapy in a long follow-up. Method Thirty-eight patients, attending the Clinical Immunology Unit and fulfilling Yamaguchi, Fautrel, or Daghor-Abbaci classification criteria for AOSD, were recruited for this study. In all patients, clinical and serological data were collected at diagnosis and every 6 months thereafter. The Pouchot score was calculated at every visit. Results Fever, arthromyalgia, and skin rash were the most frequent manifestations, followed by lymphadenopathy, sore throat, arthritis, splenomegaly, hepatic involvement, pleuropericarditis, and weight loss. As far as the disease course is concerned, 25% presented a monocyclic and 35% a polycyclic pattern, and 40% developed chronic articular involvement. Severe complications were observed at disease onset in 21% of the patients. All of the patients were treated with steroids; 74% also received conventional synthetic disease-modifying anti-rheumatic drugs (methotrexate in most cases) and 71% biological disease-modifying anti-rheumatic drugs (interleukin-1 inhibitors in most cases). Therapeutic switching for lack/loss of efficacy or adverse drug reactions was necessary in 66%. Conclusion The analysis of this cohort confirms that AOSD is a complex, severe, and heterogeneous disease. However, despite long-term treatment and comorbidities, therapies are effective and well tolerated. The therapeutic armamentarium now available allows long-lasting remission with low immunosuppression to be achieved in most patients.

Analysis of clinical manifestations and spectrum of pharmacotherapy in Moscow and St. Petersburg cohorts of patients with adult-onset Still's disease

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease of unknown etiology characterized by clinical manifestations such as fever, non-stable maculopapular rash, arthritis and/or arthralgias and leukocytosis with neutrophilia.Objective: to analyze the spectrum of clinical manifestations of AOSD and pharmacotherapy in real clinical practice.Material and methods. A cross-sectional study included 111 patients with a confirmed diagnosis of AOSD according to the Yamaguchi criteria, who were treated in two large Russian centers from 2019 to 2022: V.A. Nasonova Research Institute of Rheumatology (Moscow) and Almazov National Medical Research Centre (Saint Petersburg).Results and discussion. We analyzed the spectrum of clinical manifestations throughout the course of the disease. The spectrum of clinical manifestations of AOSD in our study was shown to be similar to the results of other studies. It was found that the frequency of the different clinical manifestations did not differ significantly.The majority of patients (74%) in our cohort received glucocorticosteroids (GC) in combination with disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs (bDMARDs). Monotherapy with GC was used in only 9% of patients. Up to 80% of patients received methotrexate (MTX) at various stages of the disease. For the treatment of patients refractory to GC and MTX therapy, bDMARDs were prescribed (44% of cases), most frequently interleukin-6 inhibitors (34%). In the St. Petersburg cohort, 13 (31.7%) of 41 patients were taking colchicine, which enabled control of disease manifestations and a reduction in the need for GC in 9 of them.Conclusion. Thus, we can draw a preliminary conclusion about the presence of steroid dependence in patients with AOSD. Up to 79.3% of AOSD patients are forced to take GC for a long period of time, which is associated with the risk of complications. Further studies on the optimal profile of bDMARDs are needed, as well as the role of colchicine as a potential therapeutic option for certain clinical and immunological subtypes of AOSD.

Deep Immunophenotyping of Circulating T and B Cells in Relapsing Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a complex systemic inflammatory disorder, categorized as an 'IL-1 driven' inflammasomapathy. Despite this, the interaction between T and B cells remains poorly understood. We conducted a study, enrolling 7 patients with relapsing AOSD and 15 healthy control subjects, utilizing deep flow cytometry analysis to examine peripheral blood T- and B-cell subsets. T-cell and B-cell subsets were significantly altered in patients with AOSD. Within CD4+ T cells, Th2 cells were decreased. Additionally, Th17 cell and follicular Th cell subsets were altered within CD45RA-CD62L+ and CD45RA-CD62L- Th cells in patients with AOSD compared to healthy controls. We identified changes in CD8+ T cell maturation and 'polarization' in AOSD patients, with an elevated presence of the TEMRA CD8+ T cell subset. Furthermore, the percentage of Tc1 cells was decreased, while the frequency of CCR6-CXCR3- Tc2 cells was elevated. Finally, we determined that the frequency of CD5+CD27- B cells was dramatically decreased in patients with AOSD compared to healthy controls. Further investigations on a large group of patients with AOSD are required to evaluate these adaptive immunity cells in the disease pathogenesis.

Increased human neutrophil lipocalin and its clinical relevance in adult-onset Still's disease.

Human neutrophil lipocalin (HNL) has been used extensively to differentiate acute bacterial infection from febrile diseases as a biomarker to reflect the activation of the neutrophil. The serum HNL levels in the adult-onset Still's disease (AOSD) patients with and without infection, as well as the healthy controls (HCs), were analyzed statistically in this study to evaluate the value of HNL for the diagnosis of AOSD. A total of 129 AOSD patients were enrolled, from whom blood samples were drawn and the AOSD diagnosis was confirmed through the review of the medical records, where the systemic score, demographic characteristics, clinical manifestations, and laboratory parameters were also collected for the patients; in addition, a total of 40 HCs were recruited among the blood donors from the healthcare center with the relevant information collected. The HNL test was done for the blood samples with the enzyme-linked immunosorbent assay and the analyses were done for the correlations of HNL with clinical manifestations and diagnostic effectiveness. The serum HNL increased significantly in the patients with only AOSD as compared with that in the HCs (139.76 ± 8.99 ng/mL vs . 55.92 ± 6.12 ng/mL; P < 0.001). The serum HNL level was correlated with the white blood cell (WBC) count ( r = 0.335, P < 0.001), neutrophil count ( r = 0.334, P < 0.001), erythrocyte sedimentation rate ( r = 0.241, P = 0.022), C-reactive protein ( r = 0.442, P < 0.0001), and systemic score ( r = 0.343, P < 0.0001) in the AOSD patients significantly. Patients with fever, leukocytosis ≥15,000/mm 3 , and myalgia in the HNL-positive group were observed relatively more than those in the HNL-negative group ( P = 0.009, P = 0.023, and P = 0.007, respectively). HNL was a more sensitive indicator than ferritin and C-reactive protein (CRP) to differentiate the AOSD patients with bacterial infection from AOSD-only patients, and the Youden index was 0.6 for HNL and 0.29 for CRP. Serum HNL can be used as a biomarker for the diagnosis of the AOSD, and HNL is also observed to be associated with the disease activity.

Interleukin-18 and Soluble Interleukin-2 Receptor Are Useful Markers for Enhanced Diagnosis of Intravascular Lymphoma

Intravascular lymphoma (IVL) is an extremely rare and aggressive form of non-Hodgkin's lymphoma characterized by lymphoma cells localized within blood vessels. Due to its rapid progression and life-threatening nature, prompt diagnosis and swift treatment are essential. However, IVL often presents with nonspecific systemic symptoms such as fever, fatigue, weight loss, skin rash, and neurological impairment without noticeable lymph node enlargement. As a result, diagnosing IVL is highly challenging, and it is frequently misdiagnosed as other conditions. A definitive diagnosis of IVL requires tissue biopsy, like a random skin biopsy, although this may not always lead to the identification of IVL from the biopsy site. Consequently, when IVL is suspected, repeated random skin biopsies may be necessary, but the optimal number of biopsies remains unknown. To avoid repetitive invasive procedures, clinical indicators that raise suspicion of IVL more aggressively in patients with nonspecific symptoms are needed. IVL often presents with clinical features that resemble adult-onset Still disease (AOSD), particularly with systemic symptoms such as fever and hemophagocytic lymphohistiocytosis (HLH). Distinguishing between IVL and AOSD is crucial, but the lack of disease-specific markers for each condition makes differentiation challenging. While recent studies suggest the utility of genetic mutation analysis using cell-free DNA for diagnosing IVL, cost and technical limitations call for the development of simpler diagnostic adjunct markers. Therefore, our study aimed to explore potential useful indicators for differentiating IVL by comparing clinical parameters used for AOSD diagnosis in both IVL and AOSD patients. We conducted a comparative analysis using clinical data and initial samples from seven patients diagnosed histologically with IVL and five AOSD patients who were confirmed negative for IVL through long-term follow-up. Additionally, samples from six healthy donors were included for comparison. The median age of IVL patients was 64 years, while AOSD patients were 47 years old, with no significant difference between the groups (p=0.668). White blood cell count, hemoglobin concentration, platelet count,lactate dehydrogenase (LDH), triglycerides, fibrinogen, and C-reactive protein showed no significant differences between IVL and AOSD patients. On the other hand, ferritin levels were significantly lower in IVL patients compared to AOSD patients (539-9164 vs. 4690-91917 ng/mL, p=0.018), and soluble interleukin-2 receptor (sIL-2R) levels were significantly higher in IVL patients (4714-37572 vs. 935-4441 U/mL, p=0.003). Furthermore, the inflammatory cytokines IL-1β, IL-6, and IL-18 were measured, and while IL-1β and IL-6 showed no significant differences between IVL and AOSD patients, IL-18 was significantly higher in AOSD (0.77x10 3-8.04x10 3 vs. 1.07x10 5-2.05x10 5 pg/mL, p=0.003) (Figure). The presence of HLH did not impact ferritin, sIL-2R, or IL-18 levels in IVL patients. Additionally, the presence of bone marrow infiltration by IVL cells did not influence the clinical parameters, including ferritin, sIL-2R, and IL-18. Furthermore, ROC analysis was performed to assess the usefulness of ferritin, sIL-2R, and IL-18 in differentiating IVL and AOSD, revealing that less than 10000 pg/mL for IL-18 and above 5000 U/mL for sIL-2R ensured a reliable differentiation between IVL and AOSD. In conclusion, IL-18 and sIL-2R showed significant differences between IVL and AOSD, suggesting their potential as useful indicators for distinguishing the two conditions. Furthermore, when investigating cases of fever of unknown origin, it is crucial to diligently perform procedures such as random skin biopsies in patients strongly suspected of having IVL based on the values of IL-18 and sIL-2R.

Efficacy and safety of 5-aminolevulinic acid in adult-onset Still's disease: A preclinical study in mice and a pilot study in humans

The study aimed to investigate the therapeutic effects of 5-aminolevulinic acid/sodium ferrous citrate (5-ALA/SFC) on adult-onset Still's disease (AOSD), specifically focusing on arthritis and macrophage activation syndrome (MAS). We used mouse models to assess the impact of 5-ALA/SFC on collagen-induced arthritis (CIA) and MAS induced by synthetic oligonucleotides containing CpG motifs (CpG-S-ODN). Additionally, we conducted a pilot study with AOSD patients receiving prednisolone (PSL) treatment and 5-ALA/SFC administration to evaluate its efficacy and safety. The 5-ALA/SFC group exhibited significantly lower joint scores in CIA mice. In CpG-S-ODN-treated mice, 5-ALA/SFC administration led to reduced hemophagocytosis and splenomegaly. The anti-inflammatory properties of 5-ALA/SFC were attributed to the suppression of CCL4 and CXCL10 production in monocytes and the induction of M2 macrophages. AOSD patients treated with 5-ALA/SFC demonstrated successful PSL tapering without adverse events. Collectively, the administration of 5-ALA/SFC showed promising potential in ameliorating arthritis and MAS in AOSD patients.

Establishment of a differential diagnosis method and an online prediction platform for AOSD and sepsis based on gradient boosting decision trees algorithm

ObjectiveThe differential diagnosis between adult-onset Still’s disease (AOSD) and sepsis has always been a challenge. In this study, a machine learning model for differential diagnosis of AOSD and sepsis was developed and an online platform was developed to facilitate the clinical application of the model.MethodsAll data were collected from 42 AOSD patients and 50 sepsis patients admitted to Affiliated Hospital of Xuzhou Medical University from December 2018 to December 2021. In addition, 5 AOSD patients and 10 sepsis patients diagnosed in our hospital after March 2022 were collected for external validation. All models were built using the scikit-learn library (version 1.0.2) in Python (version 3.9.7), and feature selection was performed using the SHAP (Shapley Additive exPlanation) package developed in Python.ResultsThe results showed that the gradient boosting decision tree(GBDT) optimization model based on arthralgia, ferritin × lymphocyte count, white blood cell count, ferritin × platelet count, and α1-acid glycoprotein/creatine kinase could well identify AOSD and sepsis. The training set interaction test (AUC: 0.9916, ACC: 0.9457, Sens: 0.9556, Spec: 0.9578) and the external validation also achieved satisfactory results (AUC: 0.9800, ACC: 0.9333, Sens: 0.8000, Spec: 1.000). We named this discrimination method AIADSS (AI-assisted discrimination of Still’s disease and Sepsis) and created an online service platform for practical operation, the website is http://cppdd.cn/STILL1/.ConclusionWe created a method for the identification of AOSD and sepsis based on machine learning. This method can provide a reference for clinicians to formulate the next diagnosis and treatment plan.

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.

Care pathway analysis and evidence gaps in adult-onset Still's disease: interviews with experts from the UK, France, Italy, and Germany.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology. Published AOSD data are limited, and clinical guidelines were lacking until recently. Managing AOSD remains largely empirical with uncertainties and high variability about the optimal care pathway. Therefore, we used a qualitative approach to collect clinical judgments from the UK, Italy, France and Germany to inform the development of an agreed care pathway. Our work aimed to decrease the uncertainty associated with clinical practice, inform future research in AOSD, and help identify standardized definitions and outcomes in this population. Semi-structured interviews and thematic analysis were conducted. Eleven clinicians were interviewed between May and July 2022: four were based in Italy, three in the UK, two in France, and two in Germany. In this work, we identified the structure of the typical care pathway for AOSD patients, which can be used to inform future economic models in AOSD. The general structure of the pathway was similar across countries. Non-steroidal anti-inflammatory drugs are prescribed during the diagnostic workup while an additive approach is commonly used in confirmed cases: corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, then biologic disease-modifying antirheumatic drugs (bDMARDs) (dose increased before switching). For severe presentations, more aggressive approaches with higher doses and early use of bDMARDs are used. The main elements of variation among countries and clinicians were the criteria used for diagnosis; order of bDMARDs and preferential treatments for articular and systemic patients; and tests for patient monitoring. There is also a lack of standardized outcome measures making comparisons and evidence synthesis challenging. We identified important evidence gaps for clinical practice, e.g., reliable tests or scores predictive of disease progression and treatment outcome, and recommendations for research, e.g., reporting of compliance rates and use of the Yamaguchi criteria for clinical study inclusion. Consensus is needed around the use of the Systemic score in clinical practice and the clinical utility of this score. A standardized definition of remission is also required in AOSD, and further research should look to identify and validate the specific laboratory markers to be considered when assessing remission.

Successful complementary therapy with traditional Chinese medicine in a patient with Qi and Jin deficiency symptoms from adult-onset Still's disease: A case report

BackgroundAdult-onset Still's disease (AOSD) is a rare yet well-documented polygenic and systemic autoinflammatory disease characterized by recurrent spiking fever, transient skin rash, arthralgia, and sore throat. Traditional Chinese medicine (TCM) holds a significant role in complementary and alternative medicine. This study presents a unique case of a female AOSD patient with concurrent Qi and fluid deficiency syndrome who received combined treatment with formulated Zhu Ye Shi Gao Decoction (ZYSGD). Case presentationIn this case, a 28-year-old female patient presented with a 15-day history of fever and skin rash accompanied by sore throat, fatigue, myalgia, and arthralgia. Additionally, leucocytosis, aminotransferase abnormalities, and elevated inflammatory factor levels were observed. Infectious diseases, solid tumors, and hematological disorders were all ruled out. Anti-infective treatments proved ineffective, leading to the final diagnosis of AOSD. Glucocorticoid therapy provided only partial relief. Consequently, formulated ZYSGD and hepatoprotective drugs were added to the glucocorticoid treatment. Subsequently, the patient's symptoms and inflammatory biomarkers showed improvement. After discharge, the patient's condition remained stable while continuing the formulated ZYSGD in combination with 4 mg of Medrolol (qd) during a 10-month follow-up period. ConclusionThis case report suggests that formulated ZYSGD could be a viable option for complementary and alternative therapy for late-stage AOSD, especially in cases involving both Qi and body fluid imbalances.

The specialized pro-resolving lipid mediator Protectin D1 affects macrophages differentiation and activity in Adult-onset Still's disease and COVID-19, two hyperinflammatory diseases sharing similar transcriptomic profiles.

COVID-19 and autoinflammatory diseases, such as Adult-onset Still's Disease (AOSD), are characterized by hyperinflammation, in which it is observed massive production and uncontrolled secretion of pro-inflammatory cytokines. The specialized pro-resolving lipid mediators (SPMs) family is one the most important processes counteracting hyperinflammation inducing tissue repair and homeostasis restoration. Among SPMs, Protectin D1 (PD1) is able to exert antiviral features, at least in animal models. The aim of this study was to compare the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with AOSD and COVID-19 and to evaluate the role of PD1 on those diseases, especially in modulating macrophages polarization. This study enrolled patients with AOSD, COVID-19, and healthy donors HDs, undergoing clinical assessment and blood sample collection. Next-generation deep sequencing was performed to identify differences in PBMCs transcripts profiles. Plasma levels of PD1 were assessed by commercial ELISA kits. Monocyte-derived macrophages were polarized into M1 and M2 phenotypes. We analyzed the effect of PD1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays. In the transcriptomes from AOSD patients and COVID-19 patients, genes involved in inflammation, lipid catabolism, and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Patients affected by COVID-19, hospitalized in intensive care unit (ICU), showed higher levels of PD1 when compared to not-ICU hospitalized patients and HDs (ICU COVID-19 vs not-ICU COVID-19, p= 0.02; HDs vs ICU COVID-19, p= 0.0006). PD1 levels were increased in AOSD patients with SS ≥1 compared to patients with SS=0 (p=0.028) and HDs (p=0.048). In vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p<0.05). Furthermore, a significant release of IL-10 and MIP-1β from M2 macrophages was observed when compared to controls (p<0.05). PD1 is able to induce pro-resolutory programs in both AOSD and COVID-19 increasing M2 polarization and inducing their activity. In particular, PD1-treated M2 macrophages from AOSD and COVID-19 patients increased the production of IL-10 and enhanced homeostatic restoration through MIP-1β production.

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.

High-titer anti-interferon-γ neutralizing autoantibodies linked to opportunistic infections in patients with adult-onset still's disease.

Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to opportunistic infections (OIs). To explore the association between anti-IFN-γ autoantibodies and OIs in patients with adult-onset Still's disease (AOSD), we aimed to examine the ability of these autoantibodies to blockade signal transducer and activator of transcription (STAT1)-phosphorylation and chemokines production. Serum titers of anti-IFN-γ autoantibodies were quantified using ELISA in 29 AOSD and 22 healthy controls (HC). The detectable autoantibodies were verified with immunoblotting assay, and their neutralizing capacity against IFN-γ-signaling was evaluated with flow-cytometry analysis and immunoblotting. IFN-γ-mediated production of supernatant chemokines, including monocyte chemoattractant protein-1 (MCP-1) and IFN-γ inducible protein-10 (IP-10), were measured by ELISA. Among 29 AOSD patients, high titers of anti-IFN-γ neutralizing autoantibodies were detectable in two patients with OIs. Immunoblotting assay revealed more effective inhibition of STAT1-phosphorylation in THP-1 cells treated with sera from autoantibody-positive AOSD patients (56.7 ± 34.79%) compared with those from HC (104.3 ±29.51%), which was also demonstrated in flow-cytometry analysis (47.13 ± 40.99 vs. 97.92 ± 9.48%, p < 0.05). Depleted serum IgG from anti-IFN-γ autoAbs-positive AOSD patients with OIs restored phosphorylated STAT-1 upon IFN-γ treatment. Sera from autoantibody-positive AOSD patients more effectively inhibited IFN-γ-mediated production of MCP-1 (45.65 pg/ml) and IP-10 (22.44 pg/ml) than sera from HC (263.1 pg/ml and 104.0 pg/ml, both p < 0.05). Serum samples showing the strongest inhibition of IFN-γ-signaling were from two patients with high-titer autoantibodies and OIs. AOSD patients have a high positive rate and titers of anti-IFN-γ autoantibodies. The remarkable blockade effect of high-titer autoantibodies on IFN-γ-mediated STAT1-phosphorylation and chemokines could make these patients susceptible to OIs.

Clinical characteristics and outcome of elderly onset adult-onset Still's disease: A 10-year retrospective study

ObjectiveOur objective was to retrospectively analyze the clinical characteristics and outcome of adult-onset Still's disease (AOSD) patients with elderly onset. MethodsRetrospective data of patients diagnosed with AOSD in our institute during 2013–2021 were analyzed. The diagnoses were based on the Yamaguchi criteria for AOSD. All long-term follow-up data were collected from medical records and phone calls. ResultsIn total, 281 AOSD patients were enrolled in this study, with the median follow-up interval of 47 months. Thirty-two (11.4%, ≥65 years) AOSD patients were classified into the elderly onset groups. Compared to the younger onset group, the percentage of patients with skin rash (p = 0.047), sore throat (p = 0.001), myalgia (p = 0.001), splenomegaly (p = 0.039), hepatosplenomegaly (p = 0.002) and the Pouchot's score (p = 0.002) were significantly lower in the elderly onset group. The death rate (p = 0.014) of elderly onset group is higher than younger onset group, and the independent risk factors of mortality in all AOSD patients were age at onset (HR: 1.115, p = 0.044), disseminated intravascular coagulation (HR: 391.576, p = 0.001) and pleuritis (HR: 23.162, p = 0.033). The probability of relapse was significantly increased in the patients with macrophage activation syndrome (MAS) compared with the patients without MAS (p < 0.001), though the different age groups of AOSD patients with MAS showed no difference in the probability of relapse (p = 0.737). ConclusionElderly onset AOSD patients were distinguished by several distinct clinical features compared to younger onset AOSD patients. The frequency of relapse and complications were similar to that of AOSD patients with elderly or younger onset. A higher mortality rate was observed in elderly onset AOSD patients, and the mortality of AOSD patients was related to age at onset, DIC and pleuritis.

A Streamlined Diagnostic Process Improved the Outcomes of Patients with Adult-Onset Still's Disease: A Single-Center Retrospective Observational Study.

The diagnosis of adult-onset Still's disease (AOSD) is often delayed due to its clinical heterogeneity and lack of pathognomic features. Hence, there is an unmet need for an efficient diagnostic process. The major aim of this study was to compare the differences in disease outcomes between two groups of AOSD patients with and without implementation of the streamlined diagnostic process (SDP). Of 172 febrile patients with skin rash and/or arthralgia, 112 individuals had AOSD. The tentative diagnosis of AOSD or non-AOSD was made with or without the SDP implementation. The selection criteria for AOSD outcomes analysis were as follows: (1) age at study entry older than 20years, (2) fulfillment of the Yamaguchi criteria for AOSD diagnosis, and (3) a follow-up period longer than 6months after initiation of therapy. Three outcome parameters were evaluated, including diagnosis lag period, the proportion of "early diagnosis," and the proportion of achieving disease remission after a 6-month therapy. The SDP was implemented for expediting AOSD diagnosis in 41 (36%) enrolled patients (SDP-implemented group). The diagnosis lag period was significantly shorter in the SDP-implemented group (median 2.0 weeks, interquartile range [IQR] 1.0-2.5weeks) than in the non-SDP-implemented group (4.0 weeks, IQR 2.0-6.0 weeks, p < 0.001). A significantly higher proportion of "early diagnosis" was also found in the SDP-implemented group (75.6%) compared with the non-SDP-implemented group (33.8%, p < 0.001). We revealed a significantly higher proportion of achieving remission in the SDP-implemented group (85.4%) compared with the non-SDP-implemented group (67.6%, p < 0.05). Logistic regression analysis revealed SDP implementation as a potential predictor of achieving disease remission. Implementing an SDP for expediting diagnosis could improve outcomes for AOSD patients. This diagnostic process increased the early diagnosis rate and led to a higher disease remission rate. However, the beneficial effects of SDP implementation need further external validation.

AIM2 and NLRC4-driven inflammasome activation in adult-onset Still's disease and the preliminary therapeutic effect exploration of carboxyamidotriazole.

This study aimed to explore the changes of four major inflammasomes in adult-onset Still's disease (AOSD) and preliminarily evaluate the therapeutic effect of carboxyamidotriazole (CAI), which has previously been reported to have the significant anti-inflammatory activity. The mRNA expressions of proinflammatory cytokines and inflammasome components in peripheral blood mononuclear cells (PBMCs) from AOSD patients and healthy controls (HC) were determined by reverse transcription-quantitative PCR. Poly(dA:dT)-induced AIM2 inflammasome and flagellin-induced NLRC4 inflammasome activation models were established in bone marrow-derived macrophages (BMDMs). The levels of cytokines in serum and culture supernatants were measured by ELISA method. The serum levels of IL-1β, IL-6, and TNF-α in AOSD patients were significantly higher than those in HC. However, the mRNA expressions of IL-1β, IL-6, IL-18, and TNF-α in PBMCs did not differ markedly in AOSD patients in comparison with HC. Significantly increased mRNA levels of AIM2, NLRC4, ASC, and caspase-1 were observed in patients with AOSD when compared with HC, while NLRP1 and NLRP3 showed no change in AOSD samples. In addition, CAI treatment could significantly reduce the levels of IL-1β, IL-6, and TNF-α secreted by AOSD PBMCs and inhibit AIM2 and NLRC4 inflammasomes activation in BMDMs. Increased levels of proinflammatory cytokines in AOSD might be associated with NLRC4 and AIM2 inflammasomes activation. CAI is likely to have the therapeutic potential for AOSD by inhibiting NLRC4 and AIM2 inflammasomes activation and reducing the proinflammatory cytokines and worthy of further investigation. These results provide new ideas for elucidating the pathogenesis of AOSD and providing specific targeted therapy. Key points • Significantly higher mRNA levels of AIM2 and NLRC4 inflammsome signaling were observed in AOSD patients compared with health controls, indicating that AIM2 and NLRC4 inflammsome activation might be related to the increased proinflammatory cytokines in AOSD. • CAI treatment markedly reduced the secretion levels of cytokines IL-1β, IL-6, and TNF-α in AOSD PBMCs and inhibited AIM2 and NLRC4 inflammasome activation.

Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis

Hyperferritinemic syndrome, an overwhelming inflammatory condition, is characterized by high ferritin levels, systemic inflammation and multi-organ dysfunction, but the pathogenic role of ferritin remains largely unknown. Here we show in an animal model that ferritin administration leads to systemic and hepatic inflammation characterized by excessive neutrophil leukocyte infiltration and neutrophil extracellular trap (NET) formation in the liver tissue. Ferritin-induced NET formation depends on the expression of peptidylarginine deiminase 4 and neutrophil elastase and on reactive oxygen species production. Mechanistically, ferritin exposure increases both overall and cell surface expression of Msr1 on neutrophil leukocytes, and also acts as ligand to Msr1 to trigger the NET formation pathway. Depletion of neutrophil leukocytes or ablation of Msr1 protect mice from tissue damage and the hyperinflammatory response, which further confirms the role of Msr1 as ferritin receptor. The relevance of the animal model is underscored by the observation that enhanced NET formation, increased Msr1 expression and signalling on neutrophil leukocytes are also characteristic to adult-onset Still’s disease (AOSD), a typical hyperferritinemic syndrome. Collectively, our findings demonstrate an essential role of ferritin in NET-mediated cytokine storm, and suggest that targeting NETs or Msr1 may benefit AOSD patients.

Genetic and pharmacological targeting of GSDMD ameliorates systemic inflammation in macrophage activation syndrome

Macrophage activation syndrome (MAS), a potentially life-threatening complication of autoimmune/autoinflammatory diseases, is characterized by the excessive expansion and activation of macrophages and cytotoxic T lymphocytes in multiple organs. Most commonly, MAS occurs in patients with systemic juvenile idiopathic arthritis and in its adult equivalent, adult-onset Still's disease (AOSD). Gasdermin D (GSDMD) is a critical pore-forming effector protein that mediates pro-inflammatory cytokine secretion via releasing its N terminal fragments to form transmembrane pores. GSDMD has been implicated in various inflammatory diseases, however, its role in MAS remains elusive. Here, we unveiled that the serum levels of GSDMD-N were elevated in patients with AOSD compared to heathy controls. In addition, the emergence of MAS features in AOSD patients resulted in further elevation. The serum levels of GSDMD were positively correlated with ferritin and interleukin-18 (IL-18). Repeated toll-like receptor 9 stimulation with unmethylated cytosine-phosphate-guanine (CpG) induced MAS symptoms in wild-type mice, including body weight loss, pancytopenia and hepatosplenomegaly. Genetic deletion and pharmacological inhibition of GSDMD ameliorated MAS symptoms in mice with the concomitant reduction of splenic and hepatic macrophage infiltration and IL-18 production. Consistent with these in vivo results, bone marrow-derived macrophages obtained from GSDMD−/− mice or treated with GSDMD inhibitor disulfiram exhibited attenuated IL-18 expression after CpG stimulation. Collectively, our findings identified GSDMD as a novel marker for MAS complication and a promising target for MAS treatment.

Inactivated SARS-CoV-2 vaccine does not increase the risk of relapse in patients with clinically inactive adult-onset Still's disease.

A succession of cases have reported flares of adult-onset Still's disease (AOSD) after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raising concerns. We aimed to investigate the impact of inactivated SARS-CoV-2 vaccines on disease activity in patients with AOSD. We prospectively enrolled clinically inactive AOSD patients visiting the outpatient clinics of our department. The patients received SARS-CoV-2 vaccines (BBIBP-CorV, Sinopharm, Beijing, China) voluntarily. The occurrence of relapse in the participants was recorded during the follow-up period, and a propensity score matching (PSM) method was used to compare the relapse rates between vaccinated and unvaccinated patients. Localized and systemic symptoms were assessed in the vaccinated patients. A total of 122 patients with inactive AOSD were included, of which 49.2% (n = 60) voluntarily received the inactivated SARS-CoV-2 vaccine. The relapse rate did not increase significantly in vaccinated patients in comparison with unvaccinated patients (after PSM: 6.8% vs 6.8%), and no relapse occurred within 1 month after vaccination. No obvious adverse reactions were reported in 75.0% of the participants, and none of the patients reported severe reactions. Increased disease activity or relapse following vaccination with inactivated SARS-CoV-2 was rare in patients with inactive AOSD. Local and systemic adverse reactions were found to be mild and self-limiting. These safety profiles of inactivated SARS-CoV-2 vaccines in patients with AOSD may assist in eliminating vaccine hesitancy and increase the vaccination rate against SARS-CoV-2.

Performance of the modified Systemic Manifestation Score for systemic juvenile idiopathic arthritis in Adult-onset Still's disease.

To compare the ability of the modified Systemic Manifestation Score (mSMS) and the mPouchot score to distinguish adult-onset Still's disease (AOSD) with high disease severity in a large cohort. We scored the disease severity of 174 patients and categorized them into high and low disease severity states. The correlation of mSMS and mPouchot score with ESR, CRP, ferritin, liver function tests, and serum cytokines was investigated. Receiver operator characteristic (ROC) curve and logistic regression analysis were performed to compare the ability of mSMS and mPouchot to distinguish patients with severe AOSD. Both mSMS and mPouchot score were positively correlated with ESR (both P < 0.001), CRP (both P < 0.0001), and serum ferritin (both P < 0.0001). Moreover, both mSMS and mPouchot score are significantly associated with liver dysfunction and high IL-18 (both P < 0.0001) and IL-6 (both P < 0.01) levels in AOSD patients. Furthermore, the area under curve (AUC) value of mSMS was significantly less than of mPouchot score (0.71 for mSMS, 0.81 for mPouchot score, P < 0.0001). Compared with mPouchot score, mSMS had higher sensitivity (75.64% vs 74.36%) and lower specificity (55.06% vs 76.40%). And mSMS had a worse performance in assessing high disease severity than mPouchot score in logistic analysis. Both scores are proven as effective to assess disease severity of AOSD. By contrast, mSMS perform worse in assessing high disease severity of AOSD patients than mPouchot score. Key Points • Both modified Systemic Manifestation Score (mSMS) and modified Pouchot score (mPouchot score) positively correlated with ESR, CRP, and serum ferritin of AOSD patients. • Both scores are significantly associated with impaired liver function and high serum cytokine levels. • mSMS had lower discriminative ability than mPouchot score to distinguish high disease severity of AOSD patients.