Abstract Background To evaluate comparative effectiveness of methotrexate (MTX), calcineurin inhibitors (CNI), Janus kinase inhibitors (JAKi), and biologics for the first-line therapies in adult-onset Still’s disease (AOSD) in real-world settings. Methods Two AOSD cohorts were retrospectively analysed. First, effectiveness of first-line biological versus non-biologic modulator was validated using overlap weighting of propensity scores in the Shanghai AOSD cohort. To compare AOSD treatment strategies (MTX, CNI, JAKi, biologics), we pooled data from the Shanghai and Erlangen cohorts, emulated a target trial, and applied doubly robust weighted regression to adjust for demographic and clinical confounders. The primary outcome was sustained event-free remission over 12 and 72 weeks. Results 124 AOSD patients were analyzed, 96 from the Shanghai and 28 from Erlangen cohort. In overlap-weighted analyses of Shanghai cohort, biologic was associated with higher sustained event-free remission and event-free state than non-biologic immune modulators ( P = 0.0065 and P = 0.0096). In the pooled analysis, biologics were linked to higher likelihood of event-free state and sustained event-free remission at weeks 12 and 72 (all P < 0.05). Pairwise comparisons confirmed the advantage of biologics over CNI (sustained event-free remission at week 72 OR 0.11, p = 0.001), with significant benefits over MTX (OR 0.12, p = 0.002) and JAKi (OR 0.14, p = 0.008) emerging at week 72 for sustained event-free remission, and more frequent glucocorticoid discontinuation than MTX and CNI (both p < 0.05). Conclusions First-line biological treatment is associated with improved sustained event-free remission compared to non-biologic treatments, such as MTX, CNI and JAKi and associated with more favorable long-term outcomes in AOSD.
OBJECTIVES: This study aimed to characterize the clinical phenotypes of adult-onset Still's disease-related lung disease (AOSD-LD) in a Chinese cohort, and to evaluate the associations of lung disease and distinct radiographic patterns with macrophage activation syndrome (MAS) and disease relapse. METHODS: In this cohort of 209 patients with AOSD, individuals were retrospectively stratified into AOSD-LD and non-lung disease groups based on radiographic findings. Clinical features associated with AOSD-LD were characterized. Multivariable Cox regression and subgroup analyses were performed to evaluate the impact of AOSD-LD on MAS and disease relapse. AOSD-LD was further categorized into acute exudative, interstitial, and suspected pulmonary hypertension (PH) patterns to assess pattern-specific outcomes. RESULTS: Lung involvement was identified in 49 (23.4%) patients, yet 69.4% were asymptomatic. Pleuritis emerged as the strongest independent risk factors of AOSD-LD (P<0.0001). AOSD-LD was independently associated with both MAS (HR = 2.62, 95% CI: 1.38-4.96, P=0.0041) and disease relapse (HR = 2.66, 95% CI: 1.50-4.71, P=0.0012) in multivariable COX analysis. Radiographically, the acute exudative pattern was most prevalent, followed by interstitial and suspected PH patterns. Prognostic stratification revealed the acute exudative pattern was strongly associated with early MAS development (P=0.0315), whereas the interstitial pattern was associated with a chronic, refractory course (P=0.0059). CONCLUSION: AOSD-LD defines a severe disease phenotype and serves as a critical independent predictor for life-threatening MAS and chronic relapse. Differentiating radiographic patterns offers valuable prognostic insights, underscoring the necessity for chest CT screening and phenotype-guided management strategies in AOSD.
A newsletter apresenta os destaques do EULAR 2026, com foco na superioridade articular do bimequizumabe frente ao risanquizumabe na artrite psoriásica e o uso inovador de CAR-T in vivo para o lúpus. Também discute um grande estudo sobre as lesões cutâneas atípicas na Doença de Still e a rápida resposta dermatológica do brepocitinibe na dermatomiosite.
The development and implementation of genetic testing has revolutionized the diagnostic landscape of autoinflammatory diseases, leading to an exponential increase in the identification of disease-associated genetic variants. Yet a substantial proportion of these are considered variants of uncertain significance (VUS), complicating both diagnosis and therapeutic decision-making. This challenge is relevant not only for monogenic systemic autoinflammatory diseases, but also in the context of genetically complex disorders that can involve multiple low-penetrance variants. Advances in protein structure prediction tools, machine learning and artificial intelligence provide powerful computational frameworks for the classification of variants; however, their predictive accuracy must be benchmarked against functional assays, particularly with respect to gain-of-function variants. Functional screening approaches benefit from both technological progress and expanding knowledge of the innate immune pathways underlying systemic autoinflammatory diseases. Large-scale analyses of variants including multiplexed functional assays and deep mutational scanning experiments have enabled the assessment of hundreds of variants, notably in NLRP3, MEFV and ADA2, generating datasets that improve variant interpretation and genetic diagnosis. Altogether, these advances increase the potential of accurately predicting in the near future the effects of missense VUS, although numerous challenges remain to be addressed, especially those concerning our understanding of the influence of non-coding VUS in systemic autoinflammatory diseases.
Although the primary endpoint was not met, week 28 analysis showed that canakinumab treatment led to improvements in various efficacy outcome measures in Japanese patients with AOSD, with no unexpected safety signals.
This study describes a familial Still's disease-like autoinflammatory syndrome caused by a gain-of-function RIPK3 variant. Our findings establish aberrant RIPK3 activation as a driver of autoinflammation and expand the spectrum of human RIPK3-associated diseases.
Objective Cytokine storm syndrome (CSS), commonly associated with hemophagocytic lymphohistiocytosis (HLH), is a fatal hyperinflammatory syndrome. Differentiating the underlying diseases responsible for CSS is essential for timely therapeutic decisions. This study explored the clinical usefulness of serum cytokine profiling in distinguishing underlying diseases in patients with CSS. Methods Serum samples were collected from 143 adult and pediatric patients with CSS and 22 healthy controls. The cohort included patients with various diagnoses of primary and secondary HLH and Kawasaki disease (KD)‐like hyperinflammatory syndromes. Serum levels of 48 cytokines were analyzed in 97 patients using a bead‐based multiplex immunoassay (Luminex assay). Serum levels of interferon alpha (IFN‐α), interleukin‐18 (IL‐18), IL‐6, CXCL9, and soluble tumor necrosis factor receptor II (sTNF‐RII) were measured in 165 participants using enzyme‐linked immunosorbent assay (ELISA). Results Luminex assay categorized patients with CSS into five clusters based on serum cytokine patterns. ELISA revealed distinct cytokine patterns, wherein patients with histiocytic necrotizing lymphadenitis‐associated HLH and systemic lupus erythematosus‐associated macrophage activation syndrome (MAS) showed elevated IFN‐α; systemic juvenile idiopathic arthritis–associated and adult‐onset Still's disease–associated MAS, X‐linked inhibitor of apoptosis protein deficiency with HLH, and NLRC4‐associated autoinflammatory disorder exhibited higher IL‐18 levels. Additionally, KD shock syndrome had higher IL‐6 levels than the other groups. CXCL9 was significantly elevated in patients with virus‐associated HLH, familial HLH, malignant lymphoma‐associated HLH, and KD‐MAS. Multisystem inflammatory syndrome in children and toxic shock syndrome also showed moderate elevations of CXCL9 and IL‐6 levels. Conclusion Serum cytokine profiling effectively differentiates CSS subtypes, facilitating better diagnosis and personalized treatment strategies based on specific disease backgrounds. image
Objective Still disease is a rare systemic inflammatory disorder of unknown origin, characterized by episodes of uncontrolled inflammation. Although natural killer (NK) cells have been implicated in Still disease pathogenesis, their precise role remains elusive. Methods Within the framework of the Immunome Project Consortium for Autoinflammatory Disorders, we performed a comprehensive NK cell phenotyping in an international cohort comprising 121 patients with distinct systemic autoinflammatory diseases (53 with Still disease, 23 with chronic recurrent multifocal osteomyelitis, 23 with familial Mediterranean fever, and 22 with inflammation of unknown origin) and 32 healthy controls. Results Our analysis revealed a unique NK cell signature in Still disease, characterized by a reduction in NK cell frequency and elevated Fas expression, rendering them more susceptible to in vitro Fas ligand–induced apoptosis. Fas ligand was expressed by Still disease monocytes and CD38 + HLA‐DR + cycling lymphocytes. Still disease NK cells displayed a hyperactivated but exhausted phenotype, including cytokine unresponsiveness, all features not observed in the other groups. This NK cell dysfunctional profile was normalized during clinical remission. Exposure of healthy NK cells to interleukin (IL)‐12, IL‐15, and IL‐18 recapitulates the Still disease–associated phenotype, suggesting an inflammation‐driven mechanism. Transcriptomic profiling identified microRNA miR‐146a as a potential regulator of this NK cell dysfunction. Conclusion Our findings establish NK cell apoptosis, exhaustion, and cytokine unresponsiveness as defining immunologic features of Still disease, distinguishing it from other inflammatory diseases in this cohort. This dysfunctional NK cell state may underlie the heightened risk of macrophage activation syndrome in Still disease and highlights inflammatory cytokines and miR‐146a as promising therapeutic targets to mitigate disease severity and prevent life‐threatening complications. image
Objective The unknown pathophysiology and the lack of specific features for systemic juvenile idiopathic arthritis and adult‐onset Still disease (collectively known as Still disease; SD) delay diagnosis and appropriate treatment. The goal of this study was to identify features and mechanisms that distinguish SD from other systemic autoinflammatory diseases (SAID). Methods Using the SomaScan assay and RNA sequencing (RNA‐Seq), we determined the plasma proteomes and immune cell microRNA (miRNA) and RNA transcriptomes of 372 patients with SAID, respectively. Proteomic findings were validated by enzyme‐linked immunosorbent assays. SD (n = 72) and non‐SD SAIDs (n = 300) were compared to identify distinguishing features of SD. We performed integrated and unbiased analyses of all data sets using weighted gene correlation network analysis to identify feature modules that characterize SD and stratify patients. Results Elevated plasma heme oxygenase 1 (HO‐1) and interleukin‐18 (IL‐18) strongly correlate and characterize SD but do not associate with general inflammation. SD was characterized by ferroptosis in plasma, type I interferon (IFN) signaling in monocyte transcriptomes, and elevated natural killer cell miRNA‐146a‐5p, which is an IL‐18 induced miRNA. Finally, we identified feature modules that distinguish SD from other SAIDs and stratified patients with SD into two distinct subgroups not attributable to disease activity or inflammation but hemophagocytosis. Conclusion This unprecedented large omics data set of SAIDs revealed that complex interactions among hemophagocytosis, IL‐18, and type I IFN signaling characterize SD. Furthermore, two distinct subgroups in patients with SD were distinguished by the degree of hemophagocytic activity. Finally, the large proteomics and RNA‐Seq data sets generated in this study can serve as an invaluable resource for the further investigation of SD and other SAIDs. image
This study aims to explore the application of machine learning techniques in assessing macrophage activation syndrome (MAS) in Still's disease. A multicenter, observational, prospective study was conducted, including patients with Still's disease enrolled in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD Study Group and the AutoInflammatory Disease Alliance (AIDA) Network Still's Disease Registry. A total of 737 patients (age: 35.5 ± 17.8, male sex: 44.7%) with Still's disease were assessed; 11.4% were affected by MAS, and 3% had a poor prognosis. First, random forest imputation was applied to the original dataset. Subsequently, a machine-learning-driven assessment was developed to explore MAS occurrence. Collectively, regression models, an exploration decision tree, and a random forest were applied, suggesting the importance of ferritin, age, C-reactive protein (CRP), and systemic score. A logistic regression model accounting for data leakage concerns was then generated using these variables, and missing values were imputed using random forest imputation. This analysis supported the role of the selected variables, which were further combined across different clinical scenarios to estimate the probability of MAS. The highest risk of MAS was estimated for patients simultaneously characterized by age ≥ 45 years, ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and a systemic score ≥ 7, corresponding to a 34.7% probability of MAS, as well as for those characterized by ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and systemic score ≥ 7, corresponding to a 33.5% probability of MAS. A machine-learning-driven prediction of MAS was explored in Still's disease, highlighting the importance of age of onset, hyperferritinaemia, increased CRP, and multiorgan involvement. A combination of these features may suggest a clinician-friendly algorithm for stratifying the probability of
Inflammasome-mediated activation of interleukin (IL)-1β and IL-18 plays a key role in the pathogenesis of adult-onset Still's disease (AOSD), a systemic autoinflammatory disorder. The cleaved free active form of IL-18 may more accurately reflect inflammasome activity than total IL-18, which includes pro-IL-18, free active IL-18, and IL-18 bound to IL-18-binding protein. This study aimed to measure serum active IL-18 levels in patients with AOSD and evaluate their clinical and diagnostic significance. Serum samples were obtained from 47 untreated patients with AOSD, 42 patients with rheumatoid arthritis (RA), 9 patients with familial Mediterranean fever (FMF), and 26 healthy controls (HCs). Active IL-18 was quantified using a specific ELISA detecting cleaved, biologically active IL-18, and 69 cytokines were analyzed in patients with AOSD using a multiplex suspension array. Correlations between active IL-18 and other cytokines, clinical parameters, and the reactive hemophagocytic syndrome diagnostic score (HScore) were evaluated, and discriminative performance was assessed using receiver operating characteristic analysis. Serum levels of active IL-18 were significantly higher in patients with AOSD than in those with RA, FMF, and HCs (all p < 0.001). Active IL-18 levels positively correlated with the Pouchot score (p < 0.001), serum ferritin level (p = 0.004), and C-reactive protein level (p = 0.004) and decreased significantly after immunosuppressive therapy (p = 0.003). Active IL-18 significantly and positively correlated with total IL-18, macrophage colony-stimulating factor, basic fibroblast growth factor, leukemia inhibitory factor, chemokine (C-X-C motif) ligand 9, and IL-12 (p40), all of which were significantly correlated with the HScore. Elevated active IL-18 levels were associated with rashes and splenomegaly. Among the evaluated biomarkers, active IL-18 showed the highest diagnostic accuracy for AOSD (cutoff > 4,231.1 pg/mL; sensitivity, 89.4%; specificity, 92.9%;
Adult-onset Still disease (AOSD) is a systemic autoimmune disorder, and most patients respond well to conventional therapies, including glucocorticoids (GCs), immunosuppressants, and biologic agents. However, a small subset of patients with severe disease remains refractory to treatment and is at risk of developing life-threatening complications.
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly recognized adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. It typically presents in older males with systemic inflammation, hematologic abnormalities, and a relapsing, treatment-refractory course. Reports in younger patients remain rare, and pulmonary involvement is often misdiagnosed as infection. We present a 30-year-old man with a two-year history of recurrent scleritis, fever, cough, auricular chondritis, rash, and transfusion-dependent macrocytic anemia. Despite multiple immunosuppressants and broad-spectrum antimicrobials, symptoms persisted. Imaging revealed relapsing bilateral ground-glass pulmonary infiltrates, and repeated microbiologic studies were negative. Bone marrow showed vacuolated precursors and cytogenetic abnormalities. A somatic UBA1 mutation (NM_003334 exon3 c.121A>G p.M41V) was detected with high variant allele frequency in blood and marrow, and notably, also in bronchoalveolar lavage cells. The patient was diagnosed with VEXAS syndrome with early myelodysplastic features. Tocilizumab induced transient improvement, but disease relapse followed. He is currently being evaluated for allogeneic hematopoietic stem cell transplantation (AHSCT). This case represents one of the youngest patients reported with VEXAS syndrome and provides rare evidence of UBA1 mutation in pulmonary cells, supporting the concept of tissue-level clonal inflammation. It highlights the importance of considering VEXAS in younger patients with unexplained systemic inflammation, cytopenias, and non-infectious pulmonary infiltrates, and supports early genetic testing and multidisciplinary management.
Objectives To evaluate the relationship between type I interferon (IFN‐I) stimulated gene (ISG) expression, Still's disease, and the development of lung disease (LD) and drug‐associated immune reactions (DAIR) to IL‐1/IL‐6 inhibitors. Methods Whole blood ISG expression was quantified by NanoString array. ISG‐28 scores were calculated in consecutive patients with Still's or Still's‐like disease. Exome sequencing with family‐based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. Results Among 57 patients (32 children, 25 adults), 16 had elevated ISG‐28 scores. This group exhibited higher prevalence of LD (0.44 vs. 0.1, p=0.007) and DAIR (0.63 vs. 0.17, p=0.003), and lower IL‐6 inhibitor use (0 vs. 0.25, p=0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL‐18, or current IL‐1 inhibition. The combination of HLA‐DRB1*15 with high ISG‐28 scores associated with LD and DAIR with high specificity, while absence of both biomarkers had high negative predictive value. Candidate genes from high ISG‐28 individuals were enriched in interferon‐related pathways, including autophagy, IFN‐I production, toll‐like receptor signaling, macrophage activation, cytoskeletal organization and responses to stress. Conclusion High IFN‐I expression correlates with LD and DAIR in Still's disease, linked to rare genetic variation in immune pathways. Combining high ISG‐28 with HLA‐DRB1*15 significantly improves post‐hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN‐I directed treatments in Still's disease with IFN‐I signature.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a monogenic disease of adulthood characterised by treatment-refractory systemic inflammation and progressive bone marrow failure. VEXAS syndrome is caused by acquired mutations in the UBA1 gene that are restricted to haematopoietic cells. Men aged 50 years or older are particularly susceptible to VEXAS syndrome, with prevalence estimates of approximately one in 4000 men. Perturbation of UBA1, the master enzyme of cellular ubiquitination, promotes myeloid-driven inflammation that is difficult to control with medications other than glucocorticoids. Cytokine-directed therapies (ie, IL-6 and JAK inhibitors) might temporise symptoms and allow glucocorticoid reduction. Hypomethylating agents (ie, azacytidine) can induce clinical and molecular remission in some patients, but are associated with substantial toxicities. Haematopoietic cell transplant might be effective treatment in patients who are suitable candidates. The discovery of VEXAS syndrome highlights the potential role of somatic mutations in complex inflammatory diseases.
Objective To evaluate the prognostic utility of circulating interleukin‐18 (IL‐18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in patients with Still disease (SD) receiving first‐line IL‐1 inhibitors (IL‐1i). Methods We retrospectively analyzed 66 biologic‐naive patients with SD who received first‐line treatment with IL‐1i. Plasma IL‐18 levels were measured at baseline and at 3, 6, and 12 months after IL‐1i initiation. Associations between IL‐18 levels and clinical outcomes were assessed using mixed‐effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. Results Median baseline IL‐18 levels were 61,425 pg/mL (interquartile range 16,194–235,746) and declined significantly after IL‐1 blockade ( P 45,000 pg/mL predicted active disease at 12 months (area under the curve [AUC] 0.82; P = 0.0002), MAS development within 24 months (AUC 0.78; P = 0.01), and a chronic–persistent course (AUC 0.73; P = 0.007). In multivariate models, elevated baseline IL‐18 and delayed IL‐1i initiation for more than three months independently predicted adverse outcomes. Strikingly, at three months, IL‐18 >15,000 pg/mL was a stronger predictor of chronic–persistent course (AUC 0.92; P < 0.0001), independent of clinical disease activity (odds ratio 25.6; P = 0.01), with the multivariate model explaining 67% of variance (AUC 0.95). Conclusion In biologic‐naive patients with SD, IL‐18 levels, especially reassessed three months after IL‐1i initiation, robustly predict long‐term disease activity, MAS risk, and chronic–persistent trajectory. Early measurement and dynamic monitoring of IL‐18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes. image
VEXAS syndrome is a rare, adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. Patients may present with symptoms similar to IgG4-related disease (IgG4-RD) or systemic vasculitis. We report the case of a 70-year-old man who presented with periorbital swelling, fever, and elevated serum IgG4. However, a biopsy of the lacrimal gland did not show histological evidence of IgG4-RD. Consecutively, the patient developed progressive pulmonary infiltrations, bicytopenia and leukocytoclastic vasculitis. Chest-CT showed organizing pneumonia, which was histologically proven by transbronchial lung cryobiopsy (TBLC), again excluding IgG4-RD. PET/CT revealed hypermetabolic bone marrow and bone marrow aspiration biopsy showed vacuolization of granulocytic precursor cells. Finally, genetic testing for UBA1 mutation confirmed the diagnosis of VEXAS syndrome. Treatment with ruxolitinib in addition to steroids, led to temporary stabilization but long-term prognosis was unfavorable. This case highlights the importance of considering VEXAS syndrome a relevant differential diagnosis of vasculitis and IgG4-RD in men. Furthermore, we present valuable insights into the pathophysiology of VEXAS through transmission electron microscopy (TEM) of TBLC samples.
To investigate the long-term safety and efficacy of tocilizumab, an IL-6 receptor inhibitor, in patients with adult-onset Still's disease. Patients who completed the precedent phase III trial of tocilizumab for adult-onset Still's disease were enrolled in a long-term extension (LTE) study. Patients received i.v. tocilizumab (8 mg/kg every 2 weeks) until its approval in Japan. The primary end point was safety and tolerability, and secondary endpoints included the ACR coreset response, glucocorticoid doses, tocilizumab dosing interval, remission defined as achieving ACR50 without fever and other laboratory parameters. Efficacy was assessed every 12 weeks. All 22 patients who had completed the precedent phase III trial participated in the LTE study. Sixteen (72.7%) completed the LTE study, with the mean observation period of 168.9 ± 10.8 weeks. Whereas three (13.6%) patients experienced serious adverse events, resulting in two patients withdrawn from the trial, no new safety signal was detected. Treatment efficacy was maintained through the LTE study, with the ACR70 response rate of 68.2% and 95.2% reduction in glucocorticoid doses from the start of the phase III trial and glucocorticoid-free remission of 40.9% at the last visit. Laboratory markers such as CRP and ferritin remained well controlled. The dosing interval was successfully extended in 63.6% of patients, with the overall mean tocilizumab interval at the final visit of 3.4 weeks. During the observation period, no new safety findings were observed with the long-term use of tocilizumab. Response to tocilizumab was sustained even with an extended dosing interval, with substantial glucocorticoid dose reduction or discontinuation. UMIN000018414.
To evaluate the diagnostic yield of whole-exome sequencing (WES) vs targeted gene panel (TGP) testing in patients evaluated for autoinflammation at the Great Ormond Street Hospital Autoinflammation Centre of Excellence. We retrospectively analysed 476 patients who underwent TGP testing between 2015 and 2022, and 210 patients who underwent WES between 2022 and 2025. Analysis of WES data combined: (i) a virtual gene panel of genes (germline and somatic) associated with inflammation; (ii) agnostic filtering according to ClinVar classification of pathogenicity; (iii) copy number variant analysis using ExomeDepth; and (iv) phenotype-driven prioritization using Exomiser. TGP testing identified molecular diagnoses in 71/476 patients (14.9%). WES increased the molecular diagnostic yield to 41/210 patients (19.5%). WES also enabled the discovery of novel genotype-phenotype associations. Significant incidental findings were identified in 29/210 (13.8%) of the cases, including variants predisposing to cancer or cardiomyopathy. In patients with suspected autoinflammation, WES increased diagnostic yield compared with TGP testing, while providing additional clinical value through novel gene discovery and capacity for future systematic reanalysis of unsolved cases. Incidental findings required careful and explicit a priori patient counselling and informed consent before offering WES. While there will be an inevitable shift from WES to whole-genome sequencing in the future, significant challenges remain for WGS, including costly large-data handling and storage, and uncertainty about the interpretation of variants in non-exonic regions. Our findings, therefore, demonstrate the significant clinical impact of WES for the work-up of autoinflammation, with pragmatic utility for timely return of results.
Still's disease exemplifies systemic inflammatory disorders existing on a continuum between autoinflammation and autoimmunity. This review examines Still's disease through this spectrum lens, integrating recent advances in pathogenesis, clinical heterogeneity, and therapeutic approaches. Emerging mechanistic insights reveal complex innate-adaptive immune interactions. Type I interferon signalling and neutrophil extracellular trap formation drive inflammation, while hyperferritinemia actively perpetuates disease through Msr1-mediated signaling. mTORC1 has emerged as a central integration hub converging multiple cytokine signals. Adaptive mechanisms increasingly contribute to complications: both macrophage activation syndrome and lung disease demonstrate IFNγ-dominant pathology with T cell hyperactivation. Clinical phenotyping identifies distinct patient clusters-from hyperferritinemic monocyclic to catastrophic multiorgan phenotypes-reflecting varying innate-adaptive contributions. Current classification criteria permit considerable diagnostic latitude and may inadvertently group mechanistically distinct conditions under a single diagnostic label. IL-1 and IL-6 receptor blockade remain therapeutic cornerstones, with evidence supporting early intervention during a window of opportunity. Novel approaches including IL-18 binding protein, JAK inhibitors, and IFNγ blockade show promise in refractory disease. Still's disease predominantly reflects autoinflammatory pathology driven by innate immune dysregulation, yet adaptive mechanisms contribute meaningfully to disease heterogeneity and complications. Recognition as a spectrum disorder-with variable innate-adaptive contributions across patients and disease phases-supports unification of pediatric and adult forms, guides mechanistically targeted therapies, and emphasizes the need for biomarker-driven patient stratification to enable personalized treatment approaches.
Adult-onset Still's disease is a rare, systemic inflammatory rheumatic disease characterized by recurrent fevers, arthritis, and an evanescent rash. One of the most serious hematologic derangements that can be seen with adult-onset Still's disease is macrophage activation syndrome. Macrophage activation syndrome is characterized by activation of lymphocytes, resulting in a cytokine storm and hemophagocytosis in the bone marrow, along with multi-organ failure. Adult-onset Still's disease with macrophage activation syndrome first presenting during pregnancy is exceptionally rare; here, we report two unique cases of such a presentation and review the pertinent literature. Both of our cases presented critically ill with end-organ failure, and responded to immunosuppression; fetal demise was present in one and an emergency caesarean section with a viable fetus was performed in the other patient. Maternal outcomes were favorable in both cases and both patients did well long-term with systemic therapy. Systemic immunosuppression, particularly anti-IL1 therapy, may be considered as treatment for this rare and life-threatening condition when presenting during pregnancy.
To evaluate the long-term outcomes, clinical phenotypes and factors associated with complications in Still's disease (systemic juvenile idiopathic arthritis) based on data from a 10-year single-centre cohort. This retrospective observational study included 110 patients with Still's disease/systemic juvenile idiopathic arthritis (sJIA) followed between 2015 and 2025 at a tertiary paediatric rheumatology centre. Demographic, clinical and laboratory parameters were analysed for associations with macrophage activation syndrome (MAS), interstitial lung disease (ILD), disease course and treatment outcomes. Statistical analyses included non-parametric tests, correlation analyses and logistic regression. MAS occurred in 36.7% of patients, nearly half at disease onset. Serositis at diagnosis was associated with subsequent MAS, while low haemoglobin and erythrocyte sedimentation rate reflected concurrent MAS features. ILD was observed in 8.2% of patients and was strongly associated with MAS and a polycyclic disease course. Older age at onset and the presence of rash were independently associated with a polycyclic course. Early anakinra initiation was more frequent in severe cases but was not independently associated with improved long-term outcomes. This 10-year cohort demonstrates marked heterogeneity in Still's disease/sJIA. MAS and ILD frequently co-occur and indicate a more aggressive course. Clinical features such as serositis may help identify patients at risk, whereas laboratory abnormalities should be interpreted in the context of active MAS.
Still's disease (SD) is now widely recognized as a single disease spectrum encompassing both childhood- and adult-onset forms. While most comparative studies so far have focused on clinical manifestations and treatment responses, aspects related to the pathophysiology of the disease including molecular mechanisms and genetic predisposition have remained less deeply explored.In this review, we provide an integrated overview of current knowledge on the pathogenic pathways driving SD. We summarize evidence supporting their contribution across the age spectrum from children to adults, and discuss age-related trends in IL-18 and S100 proteins, recognized key-mediators of systemic inflammation.To complement the existing literature, we present novel data on IL-18 measurements collected in the context of cohort studies and clinical practice in three tertiary centers involved in SD care across the ages, showing a modest but significant age-related decline in patient IL-18 levels across sJIA and AOSD cohorts.Finally, we emphasize that both sJIA and AOSD share convergent genetic associations within the HLA class II region, although specific variants may exert different functional effects. In particular, HLA-DRB1*15 has been linked to disease susceptibility in the adult spectrum, whereas in children this specific HLA background appears to predispose to lung involvement and features of hypersensitivity.Altogether, the data presented collectively support the view that SD represents a single acquired and complex autoinflammatory disease in which both pediatric and adult forms share core pathogenic mechanisms as well as genetic associations within the HLA class II region. Nevertheless, we observed some differences between children and adults that remain difficult to interpret, as it remains unclear whether they reflect true biological variation or result from differences in study design or methodology. Further comparative, cross-cohort and longitudinal studies will be needed to
To evaluate for the first time a combination of novel colour Doppler ultrasound (CDUS), greyscale (GSUS) and oscillometric indices of angiopathy in patients with autoinflammatory syndromes (AIS). Further, to explore the associations between these markers and patient- and disease-related characteristics, as well as traditional cardiovascular (CV) risk factors. CDUS was used to assess arterial compliance markers, such as resistance index, pulsatility index (PI) and flow-velocity integral (FVI) in the common carotid artery (CCA) of AIS patients and healthy controls. Additionally, GSUS was employed to measure carotid intima-media thickness (cIMT), detect plaques and quantify total calcification surface. Oscillometry was utilized to evaluate aortic stiffness by carotid-femoral pulse wave velocity (cfPWV). Thirty-one patients with AIS and 62-matched (1:2) healthy controls were recruited. AIS patients exhibited higher CCA-PI [1.89 (0.46) vs 1.59 (0.32), P = 0.024] and peak systolic velocity (80.15 vs 64.95 cm/s, P = 0.003), compared with controls. Moreover, AIS patients not receiving biologic therapy demonstrated significantly higher cfPWV [6.99 (1.71) vs 5.86 (0.81) m/s, P = 0.001]. cfPWV and cIMT were predicted by age (cfPWV: rho = 0.573, P < 0.001; cIMT: rho = 0.675, P = 0.002), systolic arterial pressure (SAP) (cfPWV: r = 0.464, P = 0.009; cIMT: rho = 0.514, P = 0.029) and lymphadenopathy (cfPWV: eta = 0.373, P = 0.039). PI associated with nicotine (rho = 0.691, P = 0.008) and FVI (inversely) with SAP (rho = -0.522, v0.026). In the first CV surrogate marker study in AIS combining oscillometry and arterial US, patients exhibited increased carotid pulsatility and altered flow dynamics vs controls. Aortic stiffness was lower in patients receiving biologics and mainly predicted by traditional CV factors and lymphadenopathy. Angiopathy markers may reveal significant vascular abnormalities in AIS patients, improving CV screening and risk classification.