Adult-onset Still's Disease Research Articles

Efficacy of tight control strategy in the treatment of adult-onset Still disease.

Adult-onset Still's disease (AOSD) characterized by a high spiking fever, skin rash, arthritis, and leukocytosis. The aim of the present study was considering the long-term outcomes of patients with AOSD who were treated with tight control strategy with disease modifying anti-rheumatic drugs (DMARDs). Fifty-six patients with AOSD treated with tight control strategy were included. Four levels of remission were defined. Remission on-treatment was defined as the clinical remission, patient global assessment (PGA) ≤ 1, and prednisolone dose ≤ 5mg/day for at least 6months. Remission off-treatment was defined as the clinical remission and PGA ≤ 1 for at least 6months as well as discontinuation of prednisolone, DMARDs, and biologics. Sustained remission on-treatment was defined as the clinical remission, PGA ≤ 1, and prednisolone dose ≤ 5mg/day for ≥ 5years. Sustained remission off-treatment was defined as the clinical remission and PGA ≤ 1 for ≥ 5years as well as discontinuation of prednisolone, DMARDs, and biologics. Throughout a median follow-up of 47months, remission on-treatment and off-treatment were obtained in 94.6% and 44.6% of patients, respectively. Sustained remission on-treatment and off-treatment were obtained in 79.2 and 8.3% of patients, respectively. Glucocorticoids (GCs) and DMARDs were discontinued in 66.1% and 48.2% of the patients, respectively. Apart from the older age of the patients in the on-GCs group, no significant differences were observed between the groups. Our study showed that using DMARDs with tight control strategy at the presentation of AOSD may control disease activity successfully. Key Points • Using DMARDs with tight control strategy at the presentation of adult-onset Still's disease may control disease activity successfully.

A case of corticosteroid‐refractory adult‐onset Still's disease successfully controlled with tocilizumab despite transient neutropenia and thrombocytopenia

AbstractWe report a case of a 50‐year‐old woman with adult‐onset Still's disease (AOSD). Even after receiving steroid pulse therapy and high‐dose oral corticosteroid medication, the patient's serum ferritin level increased, while the number of neutrophils and platelets decreased. However, fever, erythema, sore throat, and arthralgia ceased. Therefore, we administered intravenous tocilizumab (TCZ). However, neutropenia, thrombocytopenia, and exacerbation of hyperferritinemia occurred after the first TCZ infusion. After the second TCZ infusion, the values returned to normal, and we discontinued prednisolone successfully without any flare‐ups of AOSD. We reviewed case reports describing adverse events after TCZ administration in AOSD patients.

Association of the Leukocyte Immunoglobulin-like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult-Onset Still's Disease.

ObjectiveAdult‐onset Still’s disease (AOSD) is a severe autoinflammatory disease. Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD. Functional leukocyte immunoglobulin‐like receptor A3 (LIR‐A3; gene name LILRA3) has been reported to be associated with many autoimmune diseases. We aimed to investigate the association of LILRA3 with disease susceptibility and neutrophil activation in AOSD.MethodsThe LILRA3 deletion polymorphism and its tagging single‐nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls. The impact of LILRA3 on clinical features and messenger RNA expression was evaluated. Plasma levels of LIR‐A3 were detected using enzyme‐linked immunosorbent assay (ELISA), and the correlation between LIR‐A3 plasma levels and disease activity and levels of circulating NET‐DNA was investigated. LIR‐A3–induced NETs were determined using PicoGreen double‐stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil‐like differentiated NB4 cell line transfected with LIR‐B2 small interfering RNA.ResultsThe findings from genotyping demonstrated that functional LILRA3 was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030–4.291], P = 0.034), and associated with leukocytosis (P = 0.039) and increased levels of circulating neutrophils (P = 0.027). Functional LILRA3 messenger RNA expression was higher in the peripheral blood mononuclear cells (P < 0.0001) and neutrophils (P < 0.001) of LILRA3 +/+ patients. Plasma levels of LIR‐A3 were elevated in patients with AOSD (P < 0.0001) and correlated with disease activity indicators and levels of circulating NET–DNA complexes. Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR‐A3. Moreover, NET formation was impaired in NB4 cells after knockdown of LILRB2 gene expression.ConclusionOur study provides the first evidence that functional LILRA3 is a novel genetic risk factor for the development of AOSD and that functional LIR‐A3 may play a pathogenic role by inducing formation of NETs.

Adult Onset Still Disease

Abstract Introduction. Adult Onset Still Disease (AOSD) is a systemic inflammatory disease, of unknown etiology, affecting young adults. It is, at least in part, a diagnosis of exclusion. Characterized by high fever with spikes, with or without complete defervescence outside of said spikes, arthritis, and evanescent rash. Also, sore throat, hepatomegaly, splenomegaly, serositis, lymphadenopathy might be present. Fatal risk is mainly attributed to Macrophage Activation Syndrome. Biologically its main trait is a marked inflammatory syndrome with unusually elevated ferritin levels. Case presentation. 31 year old male, known with a history of alopecia areata, treated with Diprophos, last dose one month prior to admission, with fever, odynophagia, sore throat, diffuse myalgia, debuted twelve days before. On blood samples, at admission and during his hospital stay, marked inflammatory signs are present (elevated ESR up to 100mm/h, C-reactive protein up to 37.4mg/dl and marked ferritin of 6240 ng/ml) accompanied by leukocytosis with neutrophilia, lymphopenia, low grade normochromic, normocytic anemia, thrombocytosis, slightly elevated liver function tests, cholestasis (GGT 502 U/L, ALKP 255 U/L) with normal bilirubin, D-dimers over 3000 with lowering values to 1344, spontaneous INR at 1.57. Normal values for rheumatoid factor, no antinuclear antibodies present, negative serology for hepatitis B, C, HIV, atypical bacterial infections (Chlamydia, Coxiella, Mycoplasma) Epstein-Barr Virus, syphilis, vasculitis markers (pANCA, cANCA) and anti-double stranded DNA, all coupled with 5 different hemocultures and 3 different urocultures all negative. Repeated ENT evaluation was within normal, chest X-Ray, echocardiography and CT scans of neck, thorax and abdomen reported back no significant abnormalities. Thus, by applying Yamaguchi criteria, after a complex evaluation of the case, the diagnosis is AOSD, and during his stay at the Internal Medicine department of Col ea Clinical Hospital, despite antiinflammatory, antithermic, antibiotic and corticosteroid treatment, the patient remains symptomatic, with high fever (up to 38.8 degrees Celsius) with chills and diffuse myalgias. At the indication of a rheumatologist, inside a specialty clinic, pulse-therapy with Methylprednisolone is initiated (500mgs a day for 5 days) with fever remission for more than 72 hours. The corticosteroid treatment is continued at home, with the patient self-monitoring for symptoms. Two months after corticoid therapy was initiated, the patient is almost without any symptoms (alopecia areata still present partially) and the inflammatory syndrome is greatly diminished. Conclusion. We present the case of a 31 year old male, with AOSD, defined by Yamaguchi criteria, with persistent symptomatology, mainly as high fever, without response to usual treatment, with the exception of pulse-therapy with Methylprednisolone. The diagnosis proved to be difficult, in part being one of exclusion, but also the clinical presentation, so unspecific, might easily lead to a different diagnosis.

CARD8 SNP rs11672725 Identified as a Potential Genetic Variant for Adult-Onset Still's Disease.

Adult-onset Still’s disease (AOSD), an autoinflammatory disorder, is related to the dysregulation of NLR3-containing a pyrin domain (NLRP3)-inflammasome signaling. We aimed to investigate the associations of genetic polymorphisms of NLRP3-inflammasome signaling with AOSD susceptibility and outcome and to examine their functional property. Fifty-three candidate single-nucleotide polymorphisms (SNPs) involved in NLRP3-inflammasome response were genotyped using Sequenom MassArray on the samples from 66 AOSD patients and 128 healthy controls. The significant SNPs were validated by direct sequencing using a TaqMan SNP analyzer. Serum levels of associated gene products were examined by ELISA. One SNP rs11672725 of CARD8 gene was identified to be significantly associated with AOSD susceptibility by using MassArray and subsequent replication validation (p = 3.57 × 10−7; odds ratio 3.02). Functional assays showed that serum CARD8 levels were significantly lower in AOSD patients (median, 10,524.6 pg/mL) compared to controls (13,964.1 pg/mL, p = 0.005), while levels of caspase-1, IL-1β and IL-18 were significantly higher in patients (107.1 pg/mL, 2.1 pg/mL, and 1495.8 pg/mL, respectively) than those in controls (99.0 pg/mL, 1.0 pg/mL, and 141.4 pg/mL, respectively). Patients carrying rs11672725CC genotype had significantly higher serum caspase-1 and IL-18 levels (121.3 pg/mL and 1748.6 pg/mL) compared to those with CT/TT genotypes (72.6 pg/mL, p = 0.019 and 609.3 pg/mL, p = 0.046). A higher proportion of patients with rs11672725CC genotype had a systemic pattern of disease outcome, which was linked to low CARD8 levels. A novel variant, rs11672725, of the CARD8 gene was identified as a potential genetic risk for AOSD. Patients carrying the rs11672725CC genotype and C allele had low CARD8 levels, and were predisposed to a systemic pattern with an elevated expression of inflammasome signaling.

Application of systems biology-based in silico tools to optimize treatment strategy identification in Still\u2019s disease

BackgroundSystemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) are manifestations of an autoinflammatory disorder with complex pathophysiology and significant morbidity, together also termed Still’s disease. The objective of the current study is to set in silico models based on systems biology and investigate the optimal treat-to-target strategy for Still’s disease as a proof-of-concept of the modeling approach.MethodsMolecular characteristics of Still’s disease and data on biological inhibitors of interleukin (IL)-1 (anakinra, canakinumab), IL-6 (tocilizumab, sarilumab), and glucocorticoids as well as conventional disease-modifying anti-rheumatic drugs (DMARDs, methotrexate) were used to construct in silico mechanisms of action (MoA) models by means of Therapeutic Performance Mapping System (TPMS) technology. TPMS combines artificial neuronal networks, sampling-based methods, and artificial intelligence. Model outcomes were validated with published expression data from sJIA patients.ResultsBiologicals demonstrated more pathophysiology-directed efficiency than non-biological drugs. IL-1 blockade mainly acts on proteins implicated in the innate immune system, while IL-6 signaling blockade has a weaker effect on innate immunity and rather affects adaptive immune mechanisms. The MoA models showed that in the autoinflammatory/systemic phases of Still’s disease, in which the innate immunity plays a pivotal role, the IL-1β-neutralizing antibody canakinumab is more efficient than the IL-6 receptor-inhibiting antibody tocilizumab. MoA models reproduced 67% of the information obtained from expression data.ConclusionsSystems biology-based modeling supported the preferred use of biologics as an immunomodulatory treatment strategy for Still’s disease. Our results reinforce the role for IL-1 blockade on innate immunity regulation, which is critical in systemic autoinflammatory diseases. This further encourages early use on Still’s disease IL-1 blockade to prevent the development of disease or drug-related complications. Further analysis at the clinical level will validate the findings and help determining the timeframe of the window of opportunity for canakinumab treatment.

Evaluating the multivisceral involvement on adult-onset Still’s disease to retrieve imaging-based differences in patients with and without macrophage activation syndrome: results from a single-centre observational study

In this study, we aimed at describing the multivisceral involvement on adult-onset Still's disease (AOSD) to retrieve imaging-based differences in patients with and without macrophage activation syndrome (MAS). From our historical cohort, patients were assessed among those who underwent a total body CT scan. Clinical and CT scan characteristics of AOSD patients with and without MAS were compared. Out of 39 AOSD patients evaluated, 14 were complicated by MAS. These patients showed higher values of ferritin and systemic score. AOSD patients with MAS presented a higher prevalence of lung disease, hepatomegaly, splenomegaly, abdominal effusions, and lymph node enlargement than others without this complication. In addition, the presence of these manifestations significantly correlated with the systemic score, furtherly reinforcing its prognostic value. Due to the specific design of our study, our findings could be burdened by a selection bias since assessing those patients underwent a total body CT scan. Thus, these data should be prudently generalised suggesting the need of further studies to fully elucidate this issue. Our findings showed a higher prevalence of multiorgan involvement in AOSD patients with MAS, suggesting imaging-based differences, although other studies are needed to fully assess this issue. Pulmonary disease, hepatomegaly, splenomegaly, lymph node enlargement, and abdominal effusions were associated with a more aggressive subset of AOSD. Key Points •The importance of an accurate assessment AOSD multivisceral involvement is suggested since it is associated with life-threatening complications. •A higher prevalence of multiorgan involvement in AOSD patients with MAS could be recognised, than others without this complication, suggesting imaging-based differences. •AOSD multivisceral involvement may correlate with the systemic score, furtherly reinforcing its prognostic value.

Macrophage activation syndrome in patients with adult-onset Still's disease under tocilizumab treatment: A single-center observational study.

Macrophage activation syndrome (MAS) developed under tocilizumab treatment poses a diagnostic challenge. This study aims to demonstrate the frequency and the clinical features of MAS developed in patients with adult-onset Still's disease (AOSD) receiving tocilizumab. The consecutive AOSD patients treated with tocilizumab in our institution from April 2008 to March 2020 were studied. The frequency of clinically diagnosed MAS during tocilizumab treatment, their conformity to the several criteria relevant for MAS, and laboratory characteristics compared to AOSD flare were investigated. Of the 20 AOSD patients treated with tocilizumab, six developed clinically diagnosed MAS, four immediately after starting tocilizumab and two after long-term treatment. Some of them had already met the MAS criteria before starting tocilizumab. At MAS diagnosis, although some did not meet the MAS criteria due to lack of fever and/or the lower ferritin levels, all consistently showed sharp increases in ferritin along with marked abnormal changes in two or more different markers of organ damage, unlike the AOSD flares. MAS is not a rare complication in AOSD patients receiving tocilizumab. The clinical similarities between systemic AOSD and MAS, and substantial alterations in MAS features by inhibition of interleukin-6 signaling may limit the utility of the existing diagnostic/classification criteria in diagnosing MAS under tocilizumab treatment. The emergence of abnormalities in MAS-related organ damage markers with a rapid elevation of ferritin should be considered as MAS development in AOSD patients receiving tocilizumab even if the patients are afebrile or have relatively low ferritin levels.

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

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

Total metabolic lesion volume of lymph nodes measured by 18F-FDG PET/CT: a new predictor of macrophage activation syndrome in adult-onset Still\u2019s disease

BackgroundTo investigate the potential utility of quantitative parameters obtained by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the assessment of disease severity and the occurrence of macrophage activation syndrome (MAS) in adult-onset Still’s disease (AOSD).MethodsFifty-seven patients with AOSD who underwent pre-treatment 18F-FDG PET/CT were recruited in this study and compared with 60 age- and sex-matched healthy controls. Clinical features and laboratory data were recorded. The systemic score was assessed to determine the disease severity. The maximal standardized uptake value (SUVmax), metabolic lesion volume (MLV), and total lesion glycolysis (TLG) were used to evaluate the involved organs and tissues that abnormally accumulated 18F-FDG. Multivariate analysis was performed to identify the PET/CT-derived risk factors contributing to the AOSD-related MAS, and their diagnostic efficiency was evaluated.ResultsHigh 18F-FDG accumulation was observed in the bone marrow (SUVmax median, 5.10), spleen (SUVmax median, 3.70), and lymph nodes (LNs, SUVmax median, 5.55). The SUVmax of the bone marrow (rho = 0.376, p = 0.004), SUVmax of the spleen (rho = 0.450, p < 0.001), TLGtotal of LNs (rho = 0.386, p = 0.017), and MLVtotal of LNs (rho = 0.391, p = 0.015) were correlated with the systemic score. The SUVmax of the spleen (p = 0.017), TLGtotal of LNs (p = 0.045), and MLVtotal of LNs (p = 0.012) were higher in patients with MAS than in those without MAS. A MLVtotal of LNs > 62.2 (OR 27.375, p = 0.042) was an independent predictive factor for MAS with a sensitivity of 80.0% and a specificity of 93.9%.ConclusionsThe glucose metabolic level of the spleen could be an effective and easy-to-use imaging indicator of disease severity, and MLVtotal of LNs > 62.2 was a strong predictor of MAS occurrence in patients with AOSD.

English

Adult-Onset Still’s Disease (AOSD) is an uncommon multisystemic inflammatory disease of no known aetiology.1 Bywaters in 1971 was the first to describe this clinical entity.2,3 Its estimated annual incidence is 0.16 per 100,000 persons.4 AOSD has a bimodal pattern of age distribution with peaks at 15 - 25 and 36 - 46 years. This shows that young adults are mainly affected. 4 It is characterised by daily high spiking fever, evanescent salmon coloured rash, polyarthritis, leucocytosis, and negative immunological study.5 The rarity of the condition has led to a low index of suspicion among clinicians. Four cases of AOSD have been reported so far in Nigeria,6–8 with the first reported in 2015 by Akintayo et al.6 We report the fifth case of AOSD diagnosed at a rural tertiary facility in South-south Nigeria.

First manifestation of adult-onset Still's disease after COVID-19.

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder that usually affects young adults, with a bimodal peak at ages 15–25 years and 36–46 years. The disease is characterised by fever of more than 39°C, transient skin rash, leucocytosis, arthralgia, arthritis, or a combination of these symptoms.1 In addition to at least two of the aforementioned major criteria, the Yamaguchi criteria for the diagnosis of AOSD require the presence of minor criteria—ie, sore throat, lymphadenopathy, hepatomegaly or splenomegaly, abnormal liver function tests, and negative tests for antinuclear antibodies and rheumatoid factor.

The Association of Serum IL-10 Levels with the Disease Activity in Systemic-Onset Juvenile Idiopathic Arthritis Patients

Objectives Interleukin-10 (IL-10) has been suggested as a biomarker of disease activity in patients with adult-onset Still's disease (AOSD). In this study, we evaluated the serum IL-10 levels and investigated its clinical relevance in systemic-onset juvenile idiopathic arthritis (SoJIA). Methods IL-10 levels were determined in 21 patients diagnosed with SoJIA and 35 patients with fever diseases which were suspected as SoJIA, and IL-10 levels were compared between SoJIA patients with regard to disease activity, disease courses, and other biomarkers. Results Patients with SoJIA had significantly higher levels of IL-10 compared to patients with other febrile diseases. The serum levels of IL-10 were significantly higher in active SoJIA compared to inactive and positively correlated with known disease activity markers such as erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), ferritin (FER), and IL-6 levels. Moreover, the levels of IL-10 at diagnosis were significantly higher in SoJIA patients with a nonmonocyclic pattern than in patients with a monocyclic pattern. Compared to CRP, ESR, FER, and IL-6, IL-10 levels were superior in predicting monocyclic patients from nonmonocyclic patients. Conclusion Compared to other febrile diseases, SoJIA patients have markedly higher levels of IL-10 which may assist with diagnosis. And a clear association of serum IL-10 levels with disease activity and disease courses in SoJIA was found. These results suggest that serum IL-10 might be a reliable clinical marker in SoJIA.

The Pathogenic Role of Interferons in the Hyperinflammatory Response on Adult-Onset Still's Disease and Macrophage Activation Syndrome: Paving the Way towards New Therapeutic Targets.

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology affecting young adults, which is burdened by life-threatening complications, mostly macrophage activation syndrome (MAS). Interferons (IFNs) are signalling molecules that mediate a variety of biological functions from defence against viral infections, to antitumor and immunomodulatory effects. These molecules have been classified into three major types: IFN I, IFN II, IFN III, presenting specific characteristics and functions. In this work, we reviewed the role of IFNs on AOSD and MAS, focusing on their pathogenic role in promoting the hyperinflammatory response and as new possible therapeutic targets. In fact, both preclinical and clinical observations suggested that these molecules could promote the hyperinflammatory response in MAS during AOSD. Furthermore, the positive results of inhibiting IFN-γ in primary hemophagocytic lymphohistiocytosis may provide a solid rationale to arrange further clinical studies, paving the way for reducing the high mortality rate in MAS during AOSD.

Different Features of Interleukin-37 and Interleukin-18 as Disase Activity Markers of Adult-Onset Still's Disease.

The aim of this study was to evaluate the usefulness of serum interleukin (IL)-37 and IL-18 as disease activity markers of adult-onset Still’s disease (AOSD) and to compare their related clinical features. Forty-five patients with a set of high and subsequent low disease activity status of AOSD were enrolled. Modified Pouchot (mPouchot) score and serologic disease activity markers including levels of IL-37 and IL-18 were compared between high and low disease activity status. The relationships between disease activity parameters and differences in levels of cytokines according to each disease manifestation were evaluated in high disease activity status. mPouchot score and all disease activity markers including IL-37 and IL-18 significantly declined after treatment. Though both cytokines positively correlated with mPouchot score, the two did not correlate with each other in high disease activity status. IL-18 positively correlated with ferritin, AST, and LDH while IL-37 correlated better with CRP. The expression level of IL-37 was related to leukocytosis while IL-18 was related to pleuritis, pneumonitis, abnormal LFT, and hyperferritinemia. In addition, patients in the IL-18 dominant group presented with higher LDH levels and required a higher mean corticosteroid dose. In conclusion, IL-37 and IL-18 are disease activity markers reflecting different aspects of AOSD that can complement each other.

Adult-Onset Still's Disease: Clinical Aspects and Therapeutic Approach.

Adult-onset Still’s disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still’s disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.

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

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

Risk of macrophage activation syndrome in patients with adult-onset Still's disease with skin involvement: A retrospective cohort study

Smallcase series and case reports indicated that atypical persistent pruritic eruptions (PPEs), another type of skin lesions seen in adult-onset Still's disease (AOSD), imply a worse prognosis than typical evanescent rashes. To investigate clinical characteristics and macrophage activation syndrome (MAS) occurrence in AOSD with PPEs. A retrospective cohort study analyzed 150 patients with AOSD with rashes at the First Affiliated Hospital of Zhejiang University from January 2013 to December 2019. Patients with AOSD with PPEs had higher lactate dehydrogenase (492.00 U/L vs 382.00 U/L; P<.001) and ferritin (6944.10ng/ml vs 4286.60ng/ml; P=.033), and lower fibrinogen (5.05g/L vs 5.77g/L; P=.014) than those with evanescent rashes. Patients with AOSD with PPEs had a higher incidence (17.4% vs 3.1%, P=.006) and cumulative event rate for MAS (P=.008) and tended to receive high-dose glucocorticoid (36% vs 20.3%; P=.036). Multivariate analysis indicated that PPEs (hazard ratio [HR], 5.519; 95% confidence interval [CI], 1.138-26.767; P=.034), aspartate aminotransferase of greater than 120 U/L (HR, 8.084; 95% CI, 1.728-37.826; P=.008), and splenomegaly (HR, 21.152; 95% CI, 2.263-197.711; P=.007) were independent risk factors for MAS. Single-center, retrospective nature, small sample size. PPEs indicated increased severity and MAS occurrence versus evanescent rashes. PPEs, aspartate aminotransferase of greater than 120 U/L, and splenomegaly were risk factors for MAS in AOSD with skin involvement.

Immune cartography of macrophage activation syndrome in the COVID-19 era.

A hyperinflammatory ‘cytokine storm’ state termed macrophage activation syndrome (MAS), culminating from a complex interplay of genetics, immunodeficiency, infectious triggers and dominant innate immune effector responses, can develop across disparate entities including systemic juvenile idiopathic arthritis (sJIA) and its counterpart adult-onset Still disease (AOSD), connective tissue diseases, sepsis, infection, cancers and cancer immunotherapy. Classifying MAS using the immunological disease continuum model, with strict boundaries that define the limits of innate and adaptive immunity, at one boundary is MAS with loss of immune function, as occurs in the ‘perforinopathies’ and some cases of sJIA–AOSD. Conversely, at the other boundary, immune hypersensitivity with gain of immune function in MHC class II-associated sJIA–AOSD and with chimeric antigen receptor (CAR) T cell therapy also triggers MAS. This provides a benchmark for evaluating severe inflammation in some patients with COVID-19 pneumonia, which cripples primary type I interferon immunity and usually culminates in a lung-centric ‘second wave’ cytokine-driven alveolitis with associated immunothrombosis; this phenomenon is generally distinct from MAS but can share features with the proposed ‘loss of immune function’ MAS variant. This loss and gain of function MAS model offers immune cartography for a novel mechanistic classification of MAS with therapeutic implications.

Diagnosis and Treatment of Adult-Onset Still’s Disease

Adult-onset Still’s disease (AOSD) is an obscure disease that is usually diagnosed after the exclusion of other febrile diseases, including other autoimmune, infectious, and malignant diseases. Although definitive diagnostic criteria and treatment guidelines for AOSD are thus far lacking, the typical manifestations of AOSD have been identified and effective medications for remission and maintenance have been proposed. The pathophysiology of the AOSD is unclear, but diagnostic criteria and treatment guidelines for AOSD can be established by determining its core etiology and conducting clinical trials of previously tested immunosuppressants and biologics.