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Objective: Next-generation sequencing (NGS) panels are increasingly used for the diagnosis of monogenic systemic autoinflammatory diseases (SAIDs). However, their role in patients with adult-onset Still's disease (AOSD) remains unknown. This study aims to assess the usefulness of NGS panels in AOSD patients to improve diagnosis and management of the disease. Methods: This observational, multicenter study included all patients with AOSD diagnosis who underwent NGS panel testing in northern Spain. Clinical manifestations, laboratory parameters, complications, and therapeutic responses were recorded. Results: A total of 24 patients (16 men, 8 women) with an average age of 42.2 ± 17.9 (mean ± SD) years, in whom NGS was performed, fulfilled the Yamaguchi and/or Fautrel criteria for AOSD. The most common symptoms, apart from fever, were skin rash (75%), asthenia (91.7%), and articular manifestations (91.7%). All patients had elevated acute-phase reactant levels and hyperferritinemia. Almost all patients received oral glucocorticoids as initial therapy. Conventional disease-modifying antirheumatic drugs (cDMARDs) were used in 17 (70.8%) patients and biologic therapy in 13 (54.1%) patients. Genetic variants were observed in 5 (20.8%) patients. None of them were classified as pathogenic. Variants of uncertain significance (VUS) were identified in NOD2 (c.2104C>T and c.2251G>A), TNFRSF1A (c.224C>T), TNFAIP3 (c.1939A>C), and SCN9A (c.2617G>A). Atypical manifestations and/or therapeutic refractoriness were observed in patients carrying genetic variants, except for one patient with the TNFAIP3 VUS. Four out of five patients with VUS had a severe and refractory course of the disease and required biologic therapy. Conclusion: NGS was useful to rule out the presence of pathogenic genetic variants related to other SAIDs and to detect VUS that may help identify patients at risk for atypical and severe manifestations and poor response to conventional therapy. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Differentiating Adult‐Onset Still's Disease (AOSD) from lymphoma is challenging. A 23‐year‐old female presented with polyarthralgia, fever, rash, lymphadenopathy, and abnormal labs. She met AOSD criteria and was diagnosed with non‐Hodgkin lymphoma. Treatment led to improvement. The differentiation between Adult‐onset Still's Disease (AOSD) and lymphoma remains challenging in our context. The Faustrel score facilitates the simultaneous diagnosis of these conditions. A 23‐year‐old woman presented with chronic polyarthralgia in a febrile context. A physical examination revealed peripheral joint syndrome, a maculopapular rash on the trunk, and peripheral lymphadenopathy. Laboratory tests showed neutrophils leukocytosis, hyperferritinemia, and a glycosylated ferritin fraction of 12%. A lymph node biopsy revealed a malignant non‐Hodgkin lymphoma, and the patient met the diagnostic criteria for AOSD according to Faustrel. She received corticosteroid therapy and four courses of Rituximab. After 6 months, clinical and biological improvements were noted. It is essential to consider the possibility of an association between atypical clinical presentations of lymphoma and AOSD. [ABSTRACT FROM AUTHOR]

Objectives: To define groups and characterize differences in the prognosis of patients with adult-onset Still's disease (AOSD). Methods: We performed a retrospective cohort study. Patients with AOSD were grouped using hierarchical unsupervised cluster analysis according to age, sex, clinical features, and laboratory data. The primary endpoints were overall survival and drug-free remission rate. Results: A total of 153 patients with AOSD were placed into four clusters. Those in Cluster 1 had a young onset, tended to be female, and had fewer complications and moderate ferritin concentrations. Those in Cluster 2 had a young onset and had more complications and higher ferritin concentrations. Those in Cluster 3 had a young onset, tended to be male, and had no lymphadenopathy and fewer complications. Those in Cluster 4 had an older onset, tended to be female, and had more complications and higher ferritin concentrations. Overall survival tended to be lower (P = .0539) in Cluster 4, and drug-free remission was higher in Clusters 1, 2, and 3 [hazard ratios (HRs) 2.19, 3.37, and 3.62 vs. Cluster 4, respectively]. Conclusions: Four groups of AOSD that have distinct clinical manifestations, ferritin concentrations, severity, and drug-free remission rate were identified, which were lowest in Cluster 4. Graphical Abstract [ABSTRACT FROM AUTHOR]

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome is characterized by heterogeneous clinical manifestations. Due to the inflammatory nature of this condition, 18-FDG–PET (18-fluorodeoxyglucose–positron emission tomography) might be used to diagnose and monitor the disease. However, no data are available about the most common findings of PET imaging in this disease. For this reason, we summarised all the available reports of patients with VEXAS who underwent at least one PET scan and described 8 additional patients' PET from our centres. Overall, we described 35 patients' PET findings. All patients were male, with a median age of 70 years. The most frequent hypermetabolic sites on PET scans were the bone marrow (77.1%), lymph nodes (35.3%), lungs (28.6%), spleen and large vessels (22.9%), and cartilage (20%). Six patients underwent a PET scan 2.7 ± 1.5 years before VEXAS diagnosis, showing nonspecific uptake in the bone marrow. Four patients had a follow-up PET scan, showing a decrease or a disappearance of the previously identified hypermetabolic areas. In conclusion, although no specific uptake site has been found for VEXAS syndrome, PET imaging could help detect inflammatory foci that are not clinically evident. In addition, high metabolic activity in bone marrow might precede the clinical onset of the disease, shedding light on the pathogenesis of VEXAS. [ABSTRACT FROM AUTHOR]

We investigated the detailed characteristics and proportions of typical and atypical rashes in 28 patients with adult‐onset Still's disease (AOSD) by retrospectively examining the clinical symptoms and pathological features. The patients consisted of six males and 22 females aged between 23 and 85 years. The skin rashes observed in the study population were as follows: (i) typical rash in six cases, (ii) atypical rash in 19, and (iii) both typical and atypical rash in three cases (in all three cases, typical rash preceded atypical rash). Furthermore, we classified atypical rashes into persistent pruritic papules and plaques (PPPP) and others. In 22 cases of atypical rashes, 10 cases had PPPP. In a comparison between young‐onset (<65 years) (n = 16) and elderly‐onset (≥65 years) (n = 12) AOSD cases, typical rashes were observed more frequently in the young‐onset cases. Regarding atypical rashes, PPPP was significantly more common in the elderly‐onset cases. [ABSTRACT FROM AUTHOR]

Introduction: Adult-onset Still's disease is a rare systemic autoinflammatory disease. We present a case of a young man with a constellation of symptoms and myopericarditis as a complication of this disease. Case: A 36-year-old Hispanic man with no significant past medical history developed a quotidian fever pattern following an upper respiratory tract infection. He initially presented with chest pain concerning for myocardial infarction and underwent cardiac catheterization, which revealed non-obstructive coronary artery disease. He was found to have myopericarditis, significant neutrophilic leukocytosis, and hyperferritinemia. He improved on high-dose corticosteroids but developed steroid-induced psychosis, and 4 months from symptom onset, he finally received tocilizumab, which eventually induced remission without adverse reactions. Discussion: Adult-onset Still's disease should be considered in a patient with fevers of undetermined origin. Due to its multisystemic involvement, adult-onset Still's disease is often a diagnosis arrived at after an extensive cardiac, hematologic, malignant, and infectious workup. Imaging, laboratory testing, and bone marrow biopsy were necessary to rule out alternative etiologies of this patient's presentation. Steroids are the mainstay of treatment because they are easily affordable, although the high risk of adverse effects makes them less desirable. Interleukin-1 inhibitors (anakinra or canakinumab) and interleukin-6 inhibitor tocilizumab are the steroid-sparing biologic agents of choice but are cost-prohibitive. Conclusion: Adult-onset Still's disease should be considered in the differential diagnoses of fever of undetermined origin. Early identification and initiation of treatment are critical to faster recovery and prevention of progression to severe complications. Steroids remain the standard first-line therapy and should be followed by disease-modifying steroid sparing drugs. The social determinants of health may preclude their timely initiation and should alert providers of proactive ways to avoid further delays. [ABSTRACT FROM AUTHOR]

We investigated the phenotypic characteristics of human leukocyte antigen (HLA)-E-expressing macrophages, NKG2A/CD94 expression in T and natural killer (NK) cells, and their interactions in patients with adult-onset Still's disease (AOSD). Peripheral blood mononuclear cells from 22 patients with AOSD and 22 healthy controls (HC) were used. Isolated monocytes were cultured first with macrophage colony-stimulating factor to differentiate into M0 macrophages and subsequently with lipopolysaccharide/interferon-γ or interleukin-4 to differentiate into M1 or M2 macrophages, respectively. HLA-E and NKG2A/CD94 expression levels were evaluated using quantitative RT-PCR and flow cytometry. HLA-E expression in M0 and M2 macrophages was significantly higher in patients with AOSD than in HC, and was positively correlated with serum C-reactive protein levels and erythrocyte sedimentation rate. NKG2A/CD94 expression in CD4 + and CD8 + T cells was significantly higher in patients with AOSD than in HC, but that in NK cells was not significantly different. In patients with AOSD, NKG2A expression in CD4 + T cells positively correlated with HLA-E expression in M0, M1, and M2 macrophages. CD94 expression in CD8 + T cells inversely correlated with HLA-E expression in M1 and M2 macrophages. NKG2A and CD94 expression in NK cells inversely correlated with HLA-E expression in M0, M1, and M2 macrophages. No significant correlation was observed between HLA-E and NKG2A/CD94 expression in HC. Increased expression of HLA-E in macrophages and NKG2A/CD94 in T cells can be observed in the inflammatory condition of AOSD. HLA-E-expressing macrophages may be associated with NKG2A/CD94 expression in T and NK cells with different correlations. [ABSTRACT FROM AUTHOR]

Abstract Introduction Adult-onset Still’s disease is a rare systemic autoinflammatory disease. We present a case of a young man with a constellation of symptoms and myopericarditis as a complication of this disease. Case A 36-year-old Hispanic man with no significant past medical history developed a quotidian fever pattern following an upper respiratory tract infection. He initially presented with chest pain concerning for myocardial infarction and underwent cardiac catheterization, which revealed non-obstructive coronary artery disease. He was found to have myopericarditis, significant neutrophilic leukocytosis, and hyperferritinemia. He improved on high-dose corticosteroids but developed steroid-induced psychosis, and 4 months from symptom onset, he finally received tocilizumab, which eventually induced remission without adverse reactions. Discussion Adult-onset Still’s disease should be considered in a patient with fevers of undetermined origin. Due to its multisystemic involvement, adult-onset Still’s disease is often a diagnosis arrived at after an extensive cardiac, hematologic, malignant, and infectious workup. Imaging, laboratory testing, and bone marrow biopsy were necessary to rule out alternative etiologies of this patient’s presentation. Steroids are the mainstay of treatment because they are easily affordable, although the high risk of adverse effects makes them less desirable. Interleukin-1 inhibitors (anakinra or canakinumab) and interleukin-6 inhibitor tocilizumab are the steroid-sparing biologic agents of choice but are cost-prohibitive. Conclusion Adult-onset Still’s disease should be considered in the differential diagnoses of fever of undetermined origin. Early identification and initiation of treatment are critical to faster recovery and prevention of progression to severe complications. Steroids remain the standard first-line therapy and should be followed by disease-modifying steroid sparing drugs. The social determinants of health may preclude their timely initiation and should alert providers of proactive ways to avoid further delays.

This study aimed to identify biomarkers to distinguish adult-onset Still’s disease (AOSD) and to predict disease phenotypes. In total, 49 patients diagnosed with AOSD and 200 patients with common diseases (controls) were included in the analysis. The levels of 69 cytokines were analyzed using a multi-suspension cytokine array. Cytokine cluster analysis was performed to identify specific molecular networks. Furthermore, random forest analysis and logistic regression analysis were used to rank cytokines based on their importance and to determine specific biomarkers for identification of AOSD patients and phenotypes. Patients with AOSD demonstrated significantly higher macrophage migration inhibitory factor (MIF) and interleukin (IL)-12(p40) serum levels than controls and patients with rheumatoid arthritis. Serum levels of chemokine (C-C motif) ligand (CCL) 8 and CCL22 were significantly lower in AOSD patients with a polycyclic systemic disease phenotype and could be differentiated with high accuracy from the other phenotypes (cutoff value for CCL8 = 122.7 pg/mL, CCL22 = 593.3 pg/mL, sensitivity 66.7%, specificity 87.1%, area under the curve 0.843). Combined MIF and IL-12(p40) levels may represent a biomarker for differentiating patients with AOSD from those with other diseases. The chemokine profiles of AOSD with a polycyclic systemic disease phenotype may differ from other phenotypes.

Elevated liver enzymes are commonly observed among adult-onset Still’s disease (AOSD), but severe acute liver failure is extremely rare. Although severe acute liver failure associated with AOSD poses a life-threatening condition, the appropriate treatment is unclear. Some case reports have demonstrated the efficacy of high-dose prednisolone (PSL) and cyclosporin A (CyA), although the adverse effects of CyA led certain patients to cease its use. Therefore, an alternative treatment option is crucial, and thus far, there have been no reports of tocilizumab (TCZ) being used for this severe phenotype. Here, we report the first case of successful treatment using TCZ as maintenance therapy for severe ALF associated with AOSD. Following initial treatment with high-dose PSL and CyA, our case was switched to TCZ due to CyA-related side effects including alopecia and tremors. Our case highlights TCZ as a potential option for maintenance therapy of this severe condition.

Introduction: Adult-onset Still's disease (AOSD) is a rare chronic autoinflammatory condition characterized by a spiking fever, arthritis, a rash, hepatosplenomegaly, lymphadenopathy, leucocytosis, and hyperferritinemia. It is sometimes accompanied by life-threatening complications like macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH). Treatment options for AOSD include glucocorticoids (GCs), immunosuppressive drugs, biological medications, and Janus kinase (JAK) inhibitors. The features that differentiate MAS/HLH from AOSD are: in MAS/HLH, a different type of fever, which is persistent, a sharp decrease in the number of leukocytes and thrombocytes, a further increase in the level of transaminases and ferritin, significant hepatosplenomegaly, lymphadenopathy, symptoms of the central nervous system (CNS), disseminated intravascular coagulation (DIC) and hemophagocytosis in the bone marrow. This study aimed to evaluate the course of AOSD, which results in MAS/HLD. Patients and methods: Nine AOSD patients, four of whom developed MAS/HLH, were treated at the Rheumatology Clinic in the Central Clinical Hospital of the Ministry of Interior Affairs from 1 January 2015 to 15 March 2020 and at the Rheumatology Clinic in the National Institute of Geriatric, Rheumatology and Rehabilitation from 1 September 2021 to 1 March 2024. Medical history, clinical data, demographic data, laboratory data, imaging data, Hscore, and treatment data were collected. Results: All the patients with MAS and an Hscore above 150 recovered. Discussion: MAS/HLH requires rapid diagnosis as well as treatment with methylprednisolone pulses, cyclosporine A, and etoposide. When comparing patients who developed MAS/HLH with those who did not, possible risk factors were identified: the presence of pregnancy (two cases) and an aggressive course of AOSD. The Hscore is a useful tool for identifying patients with MAS/HLH. [ABSTRACT FROM AUTHOR]

Objective 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. Methods Twenty-nine active AOSD patients were enrolled. Flow cytometry was used to analyse the cell populations in peripheral blood. Antibody chips were utilized to detect the protein expression profile in serum. Results 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 (HCs). 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 mitogen-activated protein kinase cascade. Conclusion 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. [ABSTRACT FROM AUTHOR]

Objective: We aimed to review the literature on the clinical presentation, renal pathology, treatment, and outcome of renal manifestations in adult-onset Still's disease (AOSD). Methods: We used PRISMA guidelines for our systematic review and included all English-language original articles from inception till September 15, 2023, on AOSD and kidney involvement in any form. Data on patient demographics, diagnostic criteria, clinical presentation, renal pathology, treatment employed including dialysis, outcome, cause of death were collected and analyzed. Results: The median age at the diagnosis of renal issues was 37, with a higher prevalence among females (58.1%). Among the cases, 28 experienced renal problems after being diagnosed with AOSD, 12 had simultaneous diagnoses of renal issues and AOSD, and in 4 cases, renal problems appeared before AOSD diagnosis. Out of the 44 cases, 36 underwent renal biopsy, revealing various pathology findings including AA amyloidosis (25%), collapsing glomerulopathy (11.4%), thrombotic microangiopathy (TMA) (11.4%), IgA nephropathy (9.1%), minimal change disease (6.8%), and others. Some cases were clinically diagnosed with TMA, proximal tubular dysfunction, or macrophage activation syndrome-related acute kidney injury. Treatment approaches varied, but glucocorticoids were commonly used. Renal involvement was associated with increased mortality and morbidity, with 6 out of 44 patients passing away, 4 progressing to end-stage renal disease (ESRD), and data on 2 cases' outcomes not available. Conclusion: Renal manifestations in AOSD are diverse but rarely studied owing to the rarity of the disease. Studies with larger data would be essential to study further on the pathogenesis and implications. [ABSTRACT FROM AUTHOR]

Aims/Background Adult-onset Still's disease (AOSD) shares similar clinical symptoms with sepsis. Thus, differentiating between AOSD and sepsis presents a great challenge while making diagnosis. This study aimed to analyse the changes in blood microbiota related to AOSD and sepsis using metagenomic next-generation sequencing (mNGS), identify potential biomarkers that distinguish AOSD from sepsis, and explore the diagnostic value of mNGS in differentiation between these two pathological conditions. Methods Clinical data of four AOSD patients and four sepsis patients treated in the Department of Rheumatology and Immunology, The Affiliated Hospital of Xuzhou Medical University between October 2021 and February 2022 were collected. The mNGS diagnostic records of these patients were analysed for microbial correlations in terms of species taxonomic structure and beta diversity by comparing blood microbiota between AOSD and sepsis. The biomarkers with the strongest capability in distinguishing the subgroups were screened using a random forest algorithm. Results There was no statistically significant differences between AOSD patients and sepsis controls in terms of gender and age (p > 0.05). A total of 91 operational taxonomic units (OTUs) were obtained. At the level of phylum, Proteobacteria, Ascomycota and Basidiomycota were present in high abundances in both groups (79.76%, 14.18% and 3.30% vs 54.03%, 32.77% and 5.81%). At the genus level, the abundances of Parainfluenzae, Aspergillus and Ralstonia were the top three highest in the AOSD group (73.88%, 10.92% and 5.48%), while Ralstonia, Aspergillus and Malassezia were ranked as the top three in the sepsis group in term of abundance (48.69%, 27.36% and 5.52%). In beta-diversity analysis, there were advances shown in visual principal coordinates analysis (PCoA) and non-metric multidimensional scaling (NMDS) between the AOSD group and sepsis group (p < 0.05), with little significant differences in the analysis of similarities (Anosim) (p > 0.05). Linear discriminant analysis effect size (LEfSe) showed that Mucoromycota, Saccharomycetes, Moraxellales, Mucorales, Xanthomonadales, Saccharomycetales, Acinetobacter, Stenotrophomonas, Yarrowia, Apophysomyces, Acinetobacter johnson, Yarrowia lipolytica, Apophysomyces variabilis and Stenotrophomonas maltophilia were more enriched in sepsis group (p < 0.05). The top five variables with the strongest capability in distinguishing between AOSD and sepsis were Acinetobacter johnsonii, Apophysomyces variabilis, Propionibacterium acnes, Stenotrophomonas maltophilia and Yarrowia lipolytica. Conclusion The blood microorganisms in AOSD were different from sepsis, and mNGS was potential to distinguish between AOSD and sepsis. [ABSTRACT FROM AUTHOR]

We use this study to analyze the trends in in-hospital length of stay, total hospital charges, and mortality among adult patients with a primary diagnosis of adult-onset still's disease (AOSD). We used the 2016–2019 National Inpatient Sample (NIS) database to conduct a retrospective study on adult AOSD patients (≥18 years old). We analyzed data on baseline patient and hospital characteristics and determined trends in in-hospital mortality, length of stay (LOS), and total hospital charges (TOTCHG). Univariate and multivariate linear and logistic regression analyses were performed to identify factors that independently affected these outcomes. Among the 1615 AOSD hospitalizations, the mean LOS was 7.34 days and the mean TOTCHG was 68,415.31 USD. Macrophage activating syndrome (MAS), disseminated intravascular coagulation (DIC), and a large hospital size were shown to statistically increase the LOS and TOTCHG, while a Native American background was shown to statistically decrease both. The mean in-hospital mortality was 0.929%, with age being the only independent predictor. Our findings reveal an increase in the economic burden of AOSD hospitalizations despite declining admissions and mortality rates. Complications, like MAS and DIC, were found to significantly contribute to this burden despite treatment advancements. Our study indicates the importance of investigating new strategies to prevent these complications. [ABSTRACT FROM AUTHOR]

Key Clinical Message Differentiating Adult‐Onset Still's Disease (AOSD) from lymphoma is challenging. A 23‐year‐old female presented with polyarthralgia, fever, rash, lymphadenopathy, and abnormal labs. She met AOSD criteria and was diagnosed with non‐Hodgkin lymphoma. Treatment led to improvement. Abstract The differentiation between Adult‐onset Still's Disease (AOSD) and lymphoma remains challenging in our context. The Faustrel score facilitates the simultaneous diagnosis of these conditions. A 23‐year‐old woman presented with chronic polyarthralgia in a febrile context. A physical examination revealed peripheral joint syndrome, a maculopapular rash on the trunk, and peripheral lymphadenopathy. Laboratory tests showed neutrophils leukocytosis, hyperferritinemia, and a glycosylated ferritin fraction of 12%. A lymph node biopsy revealed a malignant non‐Hodgkin lymphoma, and the patient met the diagnostic criteria for AOSD according to Faustrel. She received corticosteroid therapy and four courses of Rituximab. After 6 months, clinical and biological improvements were noted. It is essential to consider the possibility of an association between atypical clinical presentations of lymphoma and AOSD.

ObjectiveNext-generation sequencing (NGS) panels are increasingly used for the diagnosis of monogenic systemic autoinflammatory diseases (SAIDs). However, their role in patients with adult-onset Still’s disease (AOSD) remains unknown. This study aims to assess the usefulness of NGS panels in AOSD patients to improve diagnosis and management of the disease.MethodsThis observational, multicenter study included all patients with AOSD diagnosis who underwent NGS panel testing in northern Spain. Clinical manifestations, laboratory parameters, complications, and therapeutic responses were recorded.ResultsA total of 24 patients (16 men, 8 women) with an average age of 42.2 ± 17.9 (mean ± SD) years, in whom NGS was performed, fulfilled the Yamaguchi and/or Fautrel criteria for AOSD. The most common symptoms, apart from fever, were skin rash (75%), asthenia (91.7%), and articular manifestations (91.7%). All patients had elevated acute-phase reactant levels and hyperferritinemia. Almost all patients received oral glucocorticoids as initial therapy. Conventional disease-modifying antirheumatic drugs (cDMARDs) were used in 17 (70.8%) patients and biologic therapy in 13 (54.1%) patients. Genetic variants were observed in 5 (20.8%) patients. None of them were classified as pathogenic. Variants of uncertain significance (VUS) were identified in NOD2 (c.2104C>T and c.2251G>A), TNFRSF1A (c.224C>T), TNFAIP3 (c.1939A>C), and SCN9A (c.2617G>A). Atypical manifestations and/or therapeutic refractoriness were observed in patients carrying genetic variants, except for one patient with the TNFAIP3 VUS. Four out of five patients with VUS had a severe and refractory course of the disease and required biologic therapy.ConclusionNGS was useful to rule out the presence of pathogenic genetic variants related to other SAIDs and to detect VUS that may help identify patients at risk for atypical and severe manifestations and poor response to conventional therapy.

Background: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease characterized by fever, rash, arthritis, and multi-organ involvement. Macrophage activation syndrome (MAS), a serious complication of AOSD, poses significant diagnostic and therapeutic challenges. Case Presentation: A 32-year-old male was diagnosed with AOSD in 2020 after being hospitalized for a fever of unknown origin and elevated liver enzymes. The patient was initially treated with corticosteroids and methotrexate but subsequently discontinued both treatment and follow-up. In September 2023, he presented with fever, sore throat, and elevated inflammatory markers. After screening for infections, methylprednisolone (MP) treatment was initiated because of AOSD activation. The following day, the patient was admitted to the intensive care unit due to an altered state of consciousness. Brain magnetic resonance imaging revealed brainstem involvement. Empirical treatments were initiated, including intravenous MP, and immunoglobulin therapy. Due to suspected macrophage activation syndrome (MAS), anakinra (ANA) infusion was initiated. Significant improvement was observed after the ANA infusion. Conclusion: This case highlights the complex management of severe AOSD complications, emphasizing the role of early recognition, aggressive therapy, and multidisciplinary care in improving outcomes.

Abstract Introduction Emapalumab is a fully human monoclonal antibody that targets free and receptor-bound interferon-gamma (IFNγ), neutralizing its biological activity. IFNγ levels differ by orders of magnitude between patients with primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS; a form of secondary HLH) in systemic juvenile idiopathic arthritis (sJIA). Therefore, this study aimed to develop a population pharmacokinetic model for emapalumab across a patient population with a wide range of total (free and emapalumab-bound) IFNγ levels using observations from patients with primary HLH or MAS in sJIA in clinical trials. Methods Pharmacokinetic data were pooled (n = 58; 2709 observations) from studies enrolling patients administered emapalumab for primary HLH or MAS in sJIA. Patients with primary HLH were administered emapalumab 1 mg/kg (potentially increasing to 3, 6, and up to 10 mg/kg based on clinical response) every 3 days. Patients with MAS in sJIA were administered emapalumab 6 mg/kg, followed by 3 mg/kg every 3 days until day 15 and twice weekly until day 28. An earlier population PK model was re-parameterized using this data. Results The final model for emapalumab comprised a 2-compartment model with first-order elimination. Emapalumab clearance remains constant when the total IFNγ concentration (free and emapalumab-bound) is

Introduction: Emapalumab is a fully human monoclonal antibody that targets free and receptor-bound interferon-gamma (IFNγ), neutralizing its biological activity. IFNγ levels differ by orders of magnitude between patients with primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS; a form of secondary HLH) in systemic juvenile idiopathic arthritis (sJIA). Therefore, this study aimed to develop a population pharmacokinetic model for emapalumab across a patient population with a wide range of total (free and emapalumab-bound) IFNγ levels using observations from patients with primary HLH or MAS in sJIA in clinical trials. Methods: Pharmacokinetic data were pooled (n = 58; 2709 observations) from studies enrolling patients administered emapalumab for primary HLH or MAS in sJIA. Patients with primary HLH were administered emapalumab 1 mg/kg (potentially increasing to 3, 6, and up to 10 mg/kg based on clinical response) every 3 days. Patients with MAS in sJIA were administered emapalumab 6 mg/kg, followed by 3 mg/kg every 3 days until day 15 and twice weekly until day 28. An earlier population PK model was re-parameterized using this data. Results: The final model for emapalumab comprised a 2-compartment model with first-order elimination. Emapalumab clearance remains constant when the total IFNγ concentration (free and emapalumab-bound) is < ~ 10,000 pg/ml but increases proportionally to total IFNγ concentration above this threshold. Emapalumab clearance was estimated to be 0.00218, 0.00308, 0.00623 and 0.01718 l/h at total serum IFNγ concentrations of 103, 104, 105 and 106 pg/ml, respectively, with corresponding terminal half-lives of 19.2, 13.8, 7.18 and 3.12 days for a 1-year-old patient weighing 10 kg with primary HLH. The median terminal half-life for emapalumab in patients with MAS in sJIA was estimated to be 24.0 (range, 6.13–32.4) days, which is similar to observations in healthy volunteers. Conclusions: Emapalumab pharmacokinetics in patients with primary HLH and MAS in sJIA were described by a two-compartment model with fixed allometric exponents and an age-related effect. Differences in total IFNγ levels between patients with primary HLH and MAS may affect emapalumab pharmacokinetics, suggesting that each indication may require different dosing to rapidly control hyperinflammation. Trial registration: Clinicaltrials.gov identifiers: NCT01818492, NCT03311854 and NCT02069899. Plain Language Summary: Patients with a rare condition called hemophagocytic lymphohistiocytosis (HLH) produce excessive amounts of a molecule called interferon-gamma. Excessive interferon-gamma causes extreme (or hyper) inflammation, which can be fatal. A drug called emapalumab can be used to block the action of interferon-gamma. However, we need to understand how the concentration of emapalumab in the blood changes over time to ensure that the correct dose is administered when attempting to control interferon-gamma-driven hyperinflammation in patients with HLH. Because HLH is a rare condition, data from a small number of patients were used to create a mathematical model that predicts emapalumab concentrations in the blood at various times after it is administered. Importantly, the amount of interferon-gamma observed in patients with different types of HLH is highly variable, which can alter how quickly emapalumab is removed from the blood. The higher interferon-gamma levels go above a certain threshold, the faster emapalumab is removed. In particular, interferon-gamma levels generally only exceed this threshold in patients with a familial or genetic form of HLH (primary HLH). Interferon-gamma levels in patients with a type of HLH called macrophage activation syndrome, which can occur in patients with systemic juvenile idiopathic arthritis (sJIA), do not usually cross the threshold associated with faster removal of emapalumab. This means that higher dosing may be required for patients with primary HLH compared with patients who have macrophage activation syndrome in sJIA to expedite control of hyperinflammation because of differences in the rate at which emapalumab is removed from the blood. [ABSTRACT FROM AUTHOR]

Objectives Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Aim: This study addresses the challenge of predicting the course of Adult‐onset Still's disease (AoSD), a rare systemic autoinflammatory disorder of unknown origin. Precise prediction is crucial for effective clinical management, especially in the absence of specific laboratory indicators. Methods: We assessed the effectiveness of combining traditional biomarkers with the k‐medoids unsupervised clustering algorithm in forecasting the various clinical courses of AoSD—monocyclic, polycyclic, or chronic articular. This approach represents an innovative strategy in predicting the disease's course. Results: The analysis led to the identification of distinct patient profiles based on accessible biomarkers. Specifically, patients with elevated ferritin levels at diagnosis were more likely to experience a monocyclic disease course, while those with lower erythrocyte sedimentation rate could present with any of the clinical courses, monocyclic, polycyclic, or chronic articular, during follow‐up. Conclusion: The study demonstrates the potential of integrating traditional biomarkers with unsupervised clustering algorithms in understanding the heterogeneity of AoSD. These findings suggest new avenues for developing personalized treatment strategies, though further validation in larger, prospective studies is necessary. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is an uncommon inflammatory condition that lacks a universally accepted diagnostic test. The clinical presentation comprises symptoms such as fever, rash, joint pain, sore throat, swelling of lymph nodes, and enlargement of the liver and spleen. The diagnostic criteria developed by Yamaguchi and Fautrel are commonly employed because of their great sensitivity and specificity. However, there are cases in which individuals may not meet these criteria but still demonstrate symptoms of AOSD. In this case, we report an elderly patient who has been diagnosed with AOSD but does not meet the criteria for any of these criteria. We discussed the factors contributing to impaired sensitivity and put forth various suggestions to enhance the sensitivity of these criteria. [ABSTRACT FROM AUTHOR]

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.

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.

Introduction. Adult-onset Still’s disease (AOSD), a systemic inflammatory disorder, often represents a heterogeneous entity and diagnosis requires the exclusion of mimicking disorders, including autoinflammatory diseases. We present a patient who meets the diagnostic criteria for AOSD and Muckle–Wells syndrome (MWS). Case outline. A 35-year-old male presented with lymphadenopathy and a chronic nonspecific rash, fever spikes, widespread arthralgia, and joint effusions. Laboratory results showed increased inflammation, leukocytosis, neutrophilia, thrombocytosis, and elevated liver enzymes, accompanied by negative immunoserological tests. Patient was diagnosed with AOSD and prednisone (15 mg/d), methotrexate (10 mg/w) and chloroquine (250 mg/d) are introduced in therapy. Due to refractory course, patient was introduced with anti IL-6 biological agent tocilizumab in 2014 (8 mg/kg monthly). However, after three doses, the drug is stopped due to disease exacerbation. In 2015, there was suspicion that there was another underlying disease from the autoinflammatory spectrum, but DNA analysis of the most common mutations in the NLRP3 gene was negative. In 2017, an ear, nose, and throat specialist confirmed bilateral sensorineural hearing loss, and in 2019, amyloidosis was confirmed after biopsy of the duodenum. Patient fulfilled a new-proposed diagnostic criteria for MWS and confirmation of mutation in NLRP3 gene is not obligatory according to Eurofever registry. Conclusion. The symptoms of AOSD and MWS partly overlap, as well as their diagnostic criteria. In chronic refractory cases of AOSD, evaluation of diagnosis should be performed and autoinflammatory syndromes must be kept in mind.

Abstract Introduction This study aimed to characterize the morbidity, hospitalization, and mortality rates among patients with adult-onset Still’s disease (AOSD) affected by coronavirus disease 2019 (COVID-19) and explore the impact of COVID-19 on the disease activity of AOSD. Methods Data on the clinical and demographic characteristics, COVID-19-related symptoms, and outcomes were retrospectively collected. Patients were stratified according to COVID-19 severity and associations between risk factors and outcomes were analyzed using multivariate logistic regression. The disease activity of patients with AOSD flares after COVID-19 was described. Results A total of 188 patients with AOSD were followed up, of whom 75.5% (n = 142) had a confirmed or highly suspected COVID-19. Patients on medium or high-dose oral glucocorticoids or Janus kinase (JAK) inhibitors were at increased risk of developing moderate to severe COVID-19. Six patients suffered flares of AOSD following COVID-19 in a short period; however, the relapse rate was not statistically increased compared with patients without COVID-19. Conclusion Patients with AOSD receiving medium or high-dose glucocorticoid therapy or JAK inhibitors had worse COVID-19 outcomes. Further work is needed to explore risk factors affecting COVID-19 outcomes and the impact of COVID-19 on disease activity in AOSD.

Adult-onset still's disease is a rare condition that is generally treated by glucocorticoids. Importantly, due to the limited established treatments, glucocorticoid-refractory cases are particularly difficult to treat. Between December 2009 and August 2022, nine patients with adult-onset Still's disease were treated with tocilizumab (tocilizumab group). The therapeutic efficacy and safety of tocilizumab initiation in the acute phase were evaluated in cases of initial onset and recurrence. We also compared the efficacy of tocilizumab with that of methotrexate (methotrexate group, n = 13), which has been the drug of choice for adjunctive therapy. Tocilizumab demonstrated the expected efficacy in all four patients who received it at relapse and in three of the five patients who received it at the initial onset. However, two patients developed macrophage activation syndrome following treatment. A comparison of treatment effects between the methotrexate and tocilizumab groups revealed that the ferritin and C-reactive protein levels, severity score, and glucocorticoid doses decreased over time in both groups; nonetheless, the tocilizumab group experienced a more stable effect. Tocilizumab is undoubtedly a valuable treatment option for adult-onset Still's disease, especially when administered at relapse. This suggests that it shows both high safety and good efficacy. Nevertheless, a larger sample size is required to validate the efficacy and safety of tocilizumab compared with those of the existing alternatives. Key Points • We examined the significance of TCZ in terms of therapeutic efficacy, reduction in glucocorticoid usage, and safety in patients with AOSD. •We compared the therapeutic efficacy of TCZ with that of MTX, which is often used to treat glucocorticoid-resistant AOSD. •TCZ is undoubtedly a valuable treatment option for AOSD, especially when administered at relapse, suggesting both high safety and good efficacy. [ABSTRACT FROM AUTHOR]

Adult-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). In 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. This 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. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to characterize the morbidity, hospitalization, and mortality rates among patients with adult-onset Still's disease (AOSD) affected by coronavirus disease 2019 (COVID-19) and explore the impact of COVID-19 on the disease activity of AOSD. Methods: Data on the clinical and demographic characteristics, COVID-19-related symptoms, and outcomes were retrospectively collected. Patients were stratified according to COVID-19 severity and associations between risk factors and outcomes were analyzed using multivariate logistic regression. The disease activity of patients with AOSD flares after COVID-19 was described. Results: A total of 188 patients with AOSD were followed up, of whom 75.5% (n = 142) had a confirmed or highly suspected COVID-19. Patients on medium or high-dose oral glucocorticoids or Janus kinase (JAK) inhibitors were at increased risk of developing moderate to severe COVID-19. Six patients suffered flares of AOSD following COVID-19 in a short period; however, the relapse rate was not statistically increased compared with patients without COVID-19. Conclusion: Patients with AOSD receiving medium or high-dose glucocorticoid therapy or JAK inhibitors had worse COVID-19 outcomes. Further work is needed to explore risk factors affecting COVID-19 outcomes and the impact of COVID-19 on disease activity in AOSD. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. Diagnosis can take a long time, especially in the presence of confounding factors, and it is, to some extent, a process of exclusion. AOSD has life-threating complications ranging from asymptomatic to severe, such as macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistocytosis (HLH). This condition is correlated with cytokine storm production and monocyte/macrophage overactivation and typically occurs with rash, pyrexia, pancytopenia, hepatosplenomegaly and systemic involvement. Exitus occurs in approximately 10% of cases. For the treatment of MAS-HLH, the Histiocyte Society currently suggests high-dose corticosteroids, with the possible addition of cyclosporine A, anti-interleukin (IL)-1, or IL-6 biological drugs; the inclusion of etoposide is recommended for the most severe conditions. In all cases, a multidisciplinary collaboration involving the resources and expertise of several specialists (e.g., rheumatologist, infectiologist, critical care medicine specialist) is advised. Herein, we provide a detailed description of the clinical case of a previously healthy young woman in which MAS developed as a dramatic onset manifestation of AOSD and whose diagnosis posed a real clinical challenge; the condition was finally resolved by applying the HLH-94 protocol (i.e., etoposide in combination with dexamethasone). [ABSTRACT FROM AUTHOR]

In most of these unknown cases, it's not that I'm completely lost. I know in a general sense that there is an inflammatory disease present. I know that there doesn't appear to be cancer in the background, or infection. I have a lengthy list of conditions that the patient does not have. But one of my most difficult tasks when I sit down with a patient at a follow-visit is to take a deep breath, adjust my glasses and admit that I don't know what's wrong." Charles Radis. The rheumatologist as detective. The Rheumatologist, 1 Feb 2015. Patients with periodic inflammation who remain undiagnosed after initial rational and targeted investigation pose a clinical conundrum. This editorial presents an approach to these cases and focuses on the recognition and diagnosis of systemic autoinflammatory diseases (SAIDs). This approach utilises genetic testing for SAIDs, recognising the presentations of non-genetic SAIDs, and empiric trials of therapy in suspected inflammatory disease. Ultimately, not achieving a final diagnosis is very common and the clinician's role is to help manage the uncertainty around this through support, follow-up and reassurance. [ABSTRACT FROM AUTHOR]

Abstract Background Adult-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. Methods We 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. Results Higher 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. Conclusions Our 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.

Abstract Background Patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) have been under-represented in studies about safety of the COVID-19 immunization. We aimed to inquire about the safety and tolerability of COVID-19 immunization in this population. Methods An anonymous online survey on closed Facebook groups for patients and parents with self-reported sJIA/AOSD was posted from June 27th until August 30th, 2022. Continuous variables were analyzed using t-tests or the Mann-Whitney U test if non-normally distributed. Fisher`s tests were used for categorical variables. Results Of a total of 167 responses, 17 were excluded. Ninety-nine patients received the COVID-19 immunization, and 51 patients did not. Patients in both immunized and unimmunized groups had a similar history of disease complications such as macrophage activation syndrome (50% vs. 49%), lung disease (17% vs. 29%), arthritis (51% vs. 50%), and pericarditis/myocarditis (10% vs. 8%). Unimmunized patients were younger (median age 8 yo vs. 12 yo, p 0.05) toward a higher risk of disease flare after COVID-19 infection among non-immunized patients (43%), compared to immunized patients (24%). Conclusions The COVID-19 immunization was well tolerated by sJIA/AOSD patients even in this group of patients with severe disease. There was a low incidence of disease flare with immunization. Most immunization side effects were mild and lasted

Abstract Introduction Patients 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). Methods A 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. Results Of 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

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Introduction: Adult-onset Still’s disease (AOSD) is a rare chronic autoinflammatory condition characterized by a spiking fever, arthritis, a rash, hepatosplenomegaly, lymphadenopathy, leucocytosis, and hyperferritinemia. It is sometimes accompanied by life-threatening complications like macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH). Treatment options for AOSD include glucocorticoids (GCs), immunosuppressive drugs, biological medications, and Janus kinase (JAK) inhibitors. The features that differentiate MAS/HLH from AOSD are: in MAS/HLH, a different type of fever, which is persistent, a sharp decrease in the number of leukocytes and thrombocytes, a further increase in the level of transaminases and ferritin, significant hepatosplenomegaly, lymphadenopathy, symptoms of the central nervous system (CNS), disseminated intravascular coagulation (DIC) and hemophagocytosis in the bone marrow. This study aimed to evaluate the course of AOSD, which results in MAS/HLD. Patients and methods: Nine AOSD patients, four of whom developed MAS/HLH, were treated at the Rheumatology Clinic in the Central Clinical Hospital of the Ministry of Interior Affairs from 1 January 2015 to 15 March 2020 and at the Rheumatology Clinic in the National Institute of Geriatric, Rheumatology and Rehabilitation from 1 September 2021 to 1 March 2024. Medical history, clinical data, demographic data, laboratory data, imaging data, Hscore, and treatment data were collected. Results: All the patients with MAS and an Hscore above 150 recovered. Discussion: MAS/HLH requires rapid diagnosis as well as treatment with methylprednisolone pulses, cyclosporine A, and etoposide. When comparing patients who developed MAS/HLH with those who did not, possible risk factors were identified: the presence of pregnancy (two cases) and an aggressive course of AOSD. The Hscore is a useful tool for identifying patients with MAS/HLH.

We use this study to analyze the trends in in-hospital length of stay, total hospital charges, and mortality among adult patients with a primary diagnosis of adult-onset still’s disease (AOSD). We used the 2016–2019 National Inpatient Sample (NIS) database to conduct a retrospective study on adult AOSD patients (≥18 years old). We analyzed data on baseline patient and hospital characteristics and determined trends in in-hospital mortality, length of stay (LOS), and total hospital charges (TOTCHG). Univariate and multivariate linear and logistic regression analyses were performed to identify factors that independently affected these outcomes. Among the 1615 AOSD hospitalizations, the mean LOS was 7.34 days and the mean TOTCHG was 68,415.31 USD. Macrophage activating syndrome (MAS), disseminated intravascular coagulation (DIC), and a large hospital size were shown to statistically increase the LOS and TOTCHG, while a Native American background was shown to statistically decrease both. The mean in-hospital mortality was 0.929%, with age being the only independent predictor. Our findings reveal an increase in the economic burden of AOSD hospitalizations despite declining admissions and mortality rates. Complications, like MAS and DIC, were found to significantly contribute to this burden despite treatment advancements. Our study indicates the importance of investigating new strategies to prevent these complications.

Key Clinical Message The present case indicates that cryoglobulinemia vasculitis should be considered in the differential diagnosis of purpura in patients with adult‐onset Still's disease (AOSD). Abstract The presence of purpura is suggested in adult‐onset Still's disease (AOSD) hematological complications of hemophagocytic syndrome, disseminated intravascular coagulation, or thrombotic microangiopathy. We herein report a case of AOSD complicated by cryoglobulinemia vasculitis presenting with purpura.

Background: Adult-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. Methods: We 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. Results: Higher 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. Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

Patients with systemic autoinflammatory diseases (sAIDs) are a section of the population at high risk of severe COVID-19 outcomes, but evidence on the efficacy of SARS-CoV-2 vaccination in this group of patients is scarce. To investigate the efficacy of SARS-CoV-2 vaccination in patients with sAIDs receiving interleukin-1 (IL-1) inhibition is important. Vaccination and infection responses from 100 sAID patients and 100 healthy controls (HCs) were analyzed. In total, 98% of patients were treated with IL-1 inhibitors at the time of vaccination (n = 98). After the second SARS-CoV-2 vaccination, sAID patients showed similar anti-SARS-CoV-2 antibody responses (mean (standard deviation (SD)): 6.7 (2.7)) compared to HCs (5.7 (2.4)) as well as similar neutralizing antibodies (85.1 ± 22.9% vs. 82.5 ± 19.7%). Anti-SARS-CoV-2 antibody responses and neutralizing antibodies were similar in sAID patients after SARS-CoV-2 infection and double vaccination. Furthermore, while antibodies increased after the first and second vaccination in sAID patients, they did not further increase after the third and fourth vaccination. No difference was found in antibody responses between anakinra and anti-IL-1 antibody treatment and the additional use of colchicine or other drugs did not impair vaccination responses. Primary and booster SARS-CoV-2 vaccinations led to protective antibody responses in sAID patients, which were at the same level of vaccination responses in HCs and in sAID patients after SARS-CoV-2 infection. Immunomodulatory treatments used in sAID do not seem to affect antibody responses to the SARS-CoV-2 vaccine. [ABSTRACT FROM AUTHOR]

Introduction: Patients 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). Methods: A 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. Results: Of 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). Conclusions: In 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 Registration: This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (Japan) as UMIN000049243. [ABSTRACT FROM AUTHOR]