Routine biomarker profile for the prediction of clinical phenotypes of adult-onset Still's disease using unsupervised clustering algorithm.

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.

Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options.

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined.

Neutrophil activation biomarker pentraxin 3 for diagnosis and monitoring of macrophage activation syndrome occurrence in adult-onset Still's disease.

Macrophage activation syndrome (MAS) is a potentially fatal consequence of adult-onset Still's disease (AOSD), driven by a cytokine storm. Efficient early diagnosis of AOSD-associated MAS requires a sensitive and specific biomarker. In this study, we demonstrated that pentraxin 3 (PTX3), an acute phase protein, was associated with AOSD disease activity and served as a biomarker for AOSD-MAS. PTX3 levels were significantly increased in AOSD patients compared to other autoimmune diseases and healthy controls. Plasma PTX3 levels showed positive correlations with inflammatory markers, the systemic score and the HScore. In active AOSD with MAS, PTX3 levels were higher compared to those in non-AOSD haemophagocytic lymphohistiocytosis (HLH) patients. Moreover, the PTX3's area under the curve value for distinguishing AOSD with MAS exceeded that of soluble interleukin-2 receptor, ferritin and C-reactive protein. Furthermore, plasma levels of PTX3 were associated with circulating NET-DNA levels. To fully understand the underlying mechanism of PTX3 prompting AOSD and AOSD-MAS progression, we discovered that neutrophils exhibited enhanced NET formation and mitogen-activated protein kinases (MAPK) pathway activation upon PTX3 stimulation. More importantly, PTX3-induced NET formation was effectively dampened by MAPK pathway inhibitors. These findings collectively revealed that PTX3 has a favorable correlation with disease activity and may serve as a potential biomarker to differentiate AOSD patients with MAS. Additionally, PTX3 induces NET release via the MAPK pathway, suggesting a pathogenic role in AOSD-MAS.

Optimal time of starting tocilizumab in acute phase of adult-onset Still's disease and comparison of its efficacy with that of methotrexate: a case series and a review of the literature.

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.

Neutrophilic Urticarial Dermatosis.

Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis that is poorly understood. It was first described by Kieffer and colleagues as an urticarial eruption that is histopathologically characterized by a perivascular and interstitial neutrophilic infiltrate with intense leukocytoclasia and without vasculitis or dermal edema. NUD clinically presents as a chronic or recurrent eruption that consists of nonpruritic macules, papules, or plaques that are pink to reddish and that resolve within 24 hours without residual pigmentation. NUD is often associated with systemic diseases such as Schnitzler syndrome, lupus erythematosus, adult-onset Still's disease, and cryopyrin-associated periodic syndromes.

Metagenomic next-generation sequencing on bronchoalveolar lavage fluid to contribute to diagnosis of subclinical pulmonary tuberculosis with scarce sputum and negative smear in a patient mimicking adult- onset still's disease: A case report.

Extremely high serum ferritin, which is regarded as a marker of adult-onset still's disease (AOSD), has been rarely observed in patients with TB. We report a case of TB diagnose by metagenomic next-generation sequencing(mNGS) who presented with clinical criteria of AOSD and extreme hyperferritinemia, which posed a diagnostic confusion. TB presenting with major clinical criteria of AOSD should be notable. Since TB remains a potentially curable disease, an awareness of its' protean manifestations is essential. A typical or even normal outcomes of clinical, microbiochemical, and radiologic evaluation should not be overlooked and dedicated diagnostic work-up should be performed for TB diagnosis. For equivocal cases, mNGS could be helpful.

The latest advances in the use of biological DMARDs to treat Still's disease.

INTRODUCTION: Currently, the therapeutic management of Still's disease, a multisystemic inflammatory rare disorder, is directed to target the inflammatory symptoms and signs of patients. The treatment varies from glucocorticoids to disease-modifying antirheumatic drugs (DMARDs), both conventional synthetic and biological (bDMARDs). Usually, in refractory patients, bDMARDs are administered. AREAS COVERED: Among bDMARDs, IL-1 and IL-6 inhibitors are frequently used, as data reported from both clinical trials and 'real-life' experiences. Recently, innovative therapeutic strategies have suggested an early administration of bDMARDs to increase the rate of clinical response and drug-free remission. Some new targets have been also proposed targeting IL-18, IFN-γ, and JAK/STAT pathway, which could be applied to Still's disease and its life-threatening evolution. EXPERT OPINION: Many lines of evidence improved the knowledge about the therapeutic management of Still's disease with bDMARDs. However, many unmet needs may be still highlighted which could provide the basis to arrange further specific research in increasing the rate of clinical response. In fact, Still's disease remains a highly heterogeneous disease suggesting possible diverse underlying pathogenic mechanisms, at least partially, and consequent different therapeutic strategies. A better patient stratification may help in arranging specific studies to improve the long-term outcome of Still's disease.

The 4th NextGen Therapies for SJIA and MAS: part 1 the elephant in the room: diagnostic/classification criteria for systemic juvenile idiopathic arthritis and adult-onset still's disease.

Currently, the criteria used to classify patients with SJIA are different from those used for AOSD. However, it has been recognized that the existing terms are too narrow, subdividing the Still's population unnecessarily between pediatric-onset and adult-onset disease and excluding an appreciable group of children in whom overt arthritis is delayed or absent. Government regulators and insurers rely upon the guidance of subject experts to provide disease definitions, and when these definitions are flawed, to provide new and better ones. The classification session at the NextGen 2022 conference helped to serve this purpose, establishing the need for a revised definitional system that transcends the fault lines that remain in existing definitions.

Recent advances and evolving concepts in Still's disease.

Still's disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still's disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still's disease and MAS. Pathological entities associated with Still's disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still's disease courses were recognized. Newer proposals of alternative Still's disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still's disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management.

Identification of discriminatory factors and construction of nomograms for differentiating AOSD and sepsis.

OBJECTIVE: This study aimed to develop nomogram prediction models to differentiate between adult-onset Still's disease (AOSD) and sepsis. METHODS: We retrospectively collected laboratory test data from 107 hospitalized patients with AOSD and sepsis at the Affiliated Hospital of Xuzhou Medical University. Multivariate binary logistic regression was used to develop nomogram models using arthralgia, WBC, APTT, creatinine, PLT, and ferritin as independent factors. The performance of the model was evaluated by the bootstrap consistency index and calibration curve. RESULTS: Model 1 had an AUC of 0.98 (95% CI, 0.96-1.00), specificity of 0.98, and sensitivity of 0.94. Model 2 had an AUC of 0.96 (95% CI, 0.93-1.00), specificity of 0.92, and sensitivity of 0.94. The fivefold cross-validation yielded an accuracy (ACC) of 0.92 and a kappa coefficient of 0.83 for Model 1, while for Model 2, the ACC was 0.87 and the kappa coefficient was 0.74. CONCLUSION: The nomogram models developed in this study are useful tools for differentiating between AOSD and sepsis. Key Points • The differential diagnosis between AOSD and sepsis has always been a challenge • Delayed treatment of AOSD may lead to serious complications • We developed two nomogram models to distinguish AOSD from sepsis, which were not previously reported • Our models can be used to guide clinical practice with good discrimination.

Clinicopathologic Features of Adult-onset Still's Disease Complicated by Severe Liver Injury.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder. Severe liver injury has rarely been reported, although liver enzyme elevation is a common complication of AOSD. We herein report four cases of relapsed AOSD with severe liver disorder by tapering or terminating corticosteroids. Liver specimens revealed robust infiltration of inflammatory cells throughout the lobule, especially cluster of differentiation (CD) 8-positive cells. Relapsed AOSD was refractory to corticosteroid reintroduction and required immunosuppressants. Severe liver injury with AOSD is pathologically characterized by extensive lobular infiltration of CD8-positive cells, and we should consider additive immunosuppressive agents on corticosteroids for treatment.

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

BACKGROUND: 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). CASE PRESENTATION: 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. CONCLUSION: 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.

Still's disease continuum from childhood to elderly: data from the international AIDA Network Still's disease registry.

OBJECTIVE: Still's disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still's disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still's disease. METHODS: Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still's disease. RESULTS: A total of 411 patients suffering from Still's disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still's disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments. CONCLUSIONS: Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still's disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still's disease is the same clinical condition arising in different ages.

[Clinical characteristics and diagnostic indicators of macrophage activation syndrome in patients with systemic lupus erythematosus and adult-onset Still's disease].

OBJECTIVE: To analyze and compare the clinical and laboratory characteristics of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD), and to evaluate the applicability of the 2016 European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization classification criteria for MAS complicating systemic juvenile idiopathic arthritis (sJIA) in different auto-immune diseases contexts and to propose new diagnostic predictive indicators. METHODS: A retrospective analysis was conducted on the clinical and laboratory data of 24 SLE patients with MAS (SLE-MAS) and 24 AOSD patients with MAS (AOSD-MAS) who were hospitalized at Peking University People's Hospital between 2000 and 2018. Age- and sex-matched SLE (50 patients) and AOSD (50 patients) diagnosed in the same period without MAS episodes were selected as controls. The cutoff values for laboratory indicators predicting SLE-MAS and AOSD-MAS were determined using receiver operating characteristic (ROC) curves. Furthermore, the laboratory diagnostic predictive values for AOSD-MAS were used to improve the classification criteria for systemic juvenile idiopathic arthritis-associated MAS (sJIA-MAS), and the applicability of the revised criteria for AOSD-MAS was explored. RESULTS: Approximately 60% of SLE-MAS and 40% of AOSD-MAS occurred within three months after the diagnosis of the underlying diseases. The most frequent clinical feature was fever. In addition to the indicators mentioned in the diagnosis criteria for hemophagocytic syndrome revised by the International Society for Stem Cell Research, the MAS patients also exhibited significantly elevated levels of aspartate aminotransferase and lactate dehydrogenase, along with a significant decrease in albumin. Hemophagocytosis was observed in only about half of the MAS patients. ROC curve analysis demonstrated that the optimal discriminative values for diagnosing MAS was achieved when SLE patients had ferritin level≥1 010 µg/L and lactate dehydroge-nase levels≥359 U/L, while AOSD patients had fibrinogen levels≤225.5 mg/dL and triglyceride levels≥2.0 mmol/L. Applying the 2016 sJIA-MAS classification criteria to AOSD-MAS yielded a diagnostic sensitivity of 100% and specificity of 62%. By replacing the less specific markers ferritin and fibrinogen in the 2016 sJIA-MAS classification criteria with new cutoff values, the revised criteria for classifying AOSD-MAS had a notable increased specificity of 86%. CONCLUSION: Secondary MAS commonly occurs in the early stages following the diagnosis of SLE and AOSD. There are notable variations in laboratory indicators among different underlying diseases, which may lead to misdiagnosis or missed diagnosis when using uniform classification criteria for MAS. The 2016 sJIA-MAS classification criteria exhibit high sensitivity but low specificity in diagnosing AOSD-MAS. Modification of the criteria can enhance its specificity.

Atypical cutaneous presentation of AOSD with persistent itchy urticaria: A case report.

RATIONALE: Adult-onset Still's disease (AOSD) is a rare multisystem disorder considered a complex autoinflammatory syndrome. The clinical and biological features of AOSD typically include a high fever with arthritic symptoms, evanescent skin rash, sore throat, striking neutrophilic leukocytosis, hyperferritinemia, and abnormal liver function. The typical rash and fever are important diagnostic clues for AOSD. Here, we report a case of atypical rash manifesting as persistent itchy urticaria. PATIENT CONCERNS: A 57-year-old female presented with a 6-day history of fever. During her hospital stay, she progressively developed rashes that were not associated with fever, primarily distributed on her back and the distal extremities, and associated with pronounced itching. The rash was initially suspected to be urticaria; however, the patient exhibited a poor response to antihistamines. After malignancies and other rheumatic diseases were excluded, the diagnosis leaned towards AOSD based on diagnostic criteria. The patient's fever was well controlled with the initiation of glucocorticoids, and no further rashes were observed. DIAGNOSES: Although the patient exhibited atypical rashes, after ruling out malignancies and other rheumatic diseases, she met 2 major and 3 minor criteria. Based on Yamaguchi's criteria, the patient was diagnosed with AOSD. INTERVENTIONS: Initially, the patient was administered an intravenous infusion of methylprednisolone at 40 mg once daily. This was later transitioned to oral administration with gradual dose reduction. OUTCOMES: Follow-up at 1 year showed no recurrence of the rash, with a stable condition and no relapse. LESSONS: This case provides valuable insights for the early diagnosis of AOSD, emphasizing the importance of considering this diagnosis even when presenting with atypical skin rash.

Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still's disease.

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-1ß, 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.

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

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

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry.

BACKGROUND: Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients. METHODS: Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters. RESULTS: K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients. CONCLUSIONS: Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', 'Uncomplicated', 'Hyperferritinemic' and 'Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group.