Abstract Background Pediatric fever of unknown origin (FUO) remains a major diagnostic challenge encompassing infectious, autoimmune and autoinflammatory as well as malignant diseases. Despite improved diagnostical procedures, no underlying disease can be identified in approximately one third of patients. Current guidelines recommend stepwise diagnostical approaches based on potential diagnostic clues (PDC+). This prospective nation-wide surveillance study aims to evaluate basic and advanced diagnostic procedures in the diagnostic of FUO. Methods and results Via the German Pediatric Surveillance Unit, children were pseudonymized enrolled based on the following inclusion criteria: fever ≥ 38.5 °C for at least five out of ten consecutive days and no identifiable cause after standard diagnostic workup. The questionnaire collected patient data, symptoms, performed diagnostic workup, and the final diagnosis, if applicable. Among 113 included children, an underlying disease was identified in 72 cases (63.7%). 26 patients (23.1%) had infections, 31 children (27.4%) had systemic onset juvenile idiopathic arthritis/Still’s disease (sJIA/SD), and 15 children (13.3%) were classified as “other diagnoses” including autoinflammatory diseases, vasculitides, and malignancies. Children with sJIA/SD presented with more clinical symptoms (mean = 4.6, SD = 2.17) compared to those with infections (mean = 2.7, SD = 1.40, p=.002). Basic diagnostic workup revealed at least one PDC + in every case (mean = 6.6). Most PDC+ (mean = 3.1, SD = 1.82) were identified by history taking and physical examination as well as by laboratory testing and blood count (mean = 2.5 PDC+, SD = 1.32). A total of 370 basic imaging investigations, e.g. abdominal ultrasound and echocardiography, provided in total 50 PDCs+ demonstrating their high diagnostical yield. Primarily in children with unclear clinical presentation advanced imaging revealed PDC+. Overall, the number of misleading PDCs (PDC-) was low (mean = 1.0, SD = 1.14) with autoantibody testing being the basic diagnostic procedure accounting for the majority of PDC-. Conclusion The results of this nation-wide surveillance study highlight the value of basic and advanced diagnostical approaches in the management of pediatric FUO. Careful history taking, physical examination, and targeted basic diagnostic testing can identify multiple PDC+ with only few misleading PDC-, which may contribute to diagnostic accuracy and avoid unnecessary testing. The findings can be introduced into guidelines in order to standardize and improve the diagnostic approaches in children with FUO.

To identify serum biomarkers associated with the development of uveitis in a German juvenile idiopathic arthritis (JIA) cohort. A convenience sample, enriched for uveitis cases, was drawn from a prospectively followed inception cohort of newly diagnosed JIA patients (ICON). Baseline serum samples were biobanked, and each was tested for conventional and novel autoantibodies using multi-analyte array technologies. Associations between uveitis occurrence, disease outcomes, and autoantibody profiles were examined. Fifty-two patients with and 141 patients without uveitis were included in the analyses. At first uveitis documentation, 26

Objectives To determine the prevalence of depressive and anxiety symptoms among young people 7 years and 9 years after inclusion in the multicentre, prospective inception cohort (ICON) of newly diagnosed patients with juvenile idiopathic arthritis (JIA) in Germany, and to identify factors associated with mental health problems at study inclusion and in the course of the disease.Methods Patients and controls (healthy peers, eg, friends of the same age and sex) from the ICON cohort (both ≥13 years) were assessed for mental health using the Patient Health Questionnaire-9 and the Generalised Anxiety Disorder Scale-7 at 7-year and 9-year follow-ups. Demographic and clinical characteristics, treatments and health-related quality of life (HRQoL) (Pediatric Quality of Life Inventory (PedsQL)) were documented at baseline and follow-up visits. Cross-sectional (analysis of variance or χ² tests at 7-year/9-year follow-up) and longitudinal analyses (generalised linear mixed models for PedsQL in follow-up from baseline) were conducted, respectively.Results A total of 344 patients (age 18.7±3.5 years, disease duration 9.2±1.8 years, 42% polyarthritis) and 224 controls (age 18.2±3.6 years) were evaluated. Moderate to severe symptoms of depression and anxiety were present in 13% and 10% of patients, respectively, compared with 7% and 2% of controls. Patients with moderate to severe psychological distress did not exhibit significantly higher physician-reported disease activity at inclusion and follow-up but reported worse patient-reported outcomes. These patients already showed reduced emotional functioning 3 months after diagnosis (p<0.001) and reported lower physical and emotional functioning (p<0.001) after the first year of specialised care compared with those without relevant mental health problems at long-term follow-up.Conclusion Poor emotional functioning at the start of care for JIA may be an indicator of future mental health issues. Therefore, HRQoL should be routinely assessed at treatment initiation to identify at-risk patients early and provide targeted support.

Systemic AutoInflammatory Diseases (SAIDs) are rare conditions characterised by impaired control of inflammatory and innate immune responses. Precision medicine is already well established for monogenic SAIDs, while personalised approaches remain elusive for those conditions with not identified genetic cause, collectively named undifferentiated SAIDs (uSAIDs).The multi-omic approach integrates findings from various ‘omics’” technologies (eg, genomics, transcriptomics, proteomics, epigenomics, immunomics), thus representing a potential way of identifying disease-specific biomarkers or complex molecular patterns, offering significant improvements in diagnosis and personalised therapies. At present, significant challenges remain in patient’s sample collection, methodological standardisation and the development of robust bioinformatics tools before the findings can be translated into clinical practice. We provide examples of successful applications of multi-omic analyses to immune-mediated disorders, address the challenges and opportunities associated with multi-omics in paediatric uSAIDs and introduce the ERA PerMed project ‘PerSAIDs’, which combines multi-omic research with artificial intelligence-based decision support solutions to further advance the diagnosis and management of SAIDs.

Objective To develop evidence-based criteria to classify patients with syndrome of undifferentiated recurrent fevers (SURF).Methods One hundred twelve patients with SURF observed in a single tertiary referral center were analyzed. Patients with genetically confirmed hereditary recurrent fever (HRF) or with periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome already analyzed for the Eurofever classification criteria were used as disease controls. A decision tree approach was tested by randomly splitting the available data in a training set and in an internal test set. An alternative model using a classical regression model was also analyzed. An external validation for both approaches was performed on 123 patients recruited from four other centers.Results The decision tree model integrating clinical and genetic data identified 91% of patients with SURF. A decision tree model based solely on clinical variables identified up to 88% of patients with SURF. The logistic regression model including genetic tests exhibited an overall accuracy of 89.2% (95% confidence interval [CI] 81.1-94.7). In contrast, the logistic regression model exclusively based on clinical manifestations displayed an overall accuracy of 66.7% (95% CI 56.1-76.1). When the classification criteria including genetic tests were applied to the external validation cohort, the model demonstrated a strong discriminative power, with areas under the receiver operating characteristic curve of 96.3% using the decision tree model and 88.0% with the logistic regression model.Conclusion The study shows the possibility of achieving evidence-based criteria that can classify SURF at least with respect to the main HRF and PFAPA syndrome and may be considered as a preliminary tool for the enrollment of more homogeneous cohorts of patients in future studies.

OBJECTIVES:To describe inequalities in health indicators relevant for quality of care to people with rheumatic and musculoskeletal diseases (RMDs) across Europe by comparing RMD health system indicators across European Alliance of Associations for Rheumatology (EULAR) member countries. METHODS:RheumaFacts is an EULAR initiative to improve the quality of care across Europe by monitoring access to and outcomes of care for people living with RMDs. In this study, we present the first edition of this longitudinal mixed-sources study initiated in 2024. A standardised form including indicators on RMD health resources and organisation, national workforce, and access to care was sent to the 40 National Scientific Rheumatology Societies who were EULAR members in 2024 was sent to the EULAR-member National Scientific Rheumatology Societies of 40 countries. Complementary data on the demographic and economic status of the various countries were extracted from open-source databases such as the WHO and World Bank datasets. Analyses were descriptive. RESULTS:Standardised report forms were returned by 36 of 40 countries (90%). The density of rheumatologists ranged from 0.8 to 6.6 per 100,000 inhabitants (median, 2.9; IQR, 2.1-3.5) across the different countries. The reimbursement of nonpharmacological care on a chronic basis was limited: physiotherapy was reimbursed in 26 of 36 countries (72%), whereas psychological support was reimbursed in only 14 of 36 countries (39%). In 94% of the countries, all conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were available. Despite all countries indicating the availability of at least 1 biologic DMARD, only 12 countries (34%) had access to all biologic DMARDs, and only 18 of 35 (51%) had access to all targeted synthetic DMARDs. CONCLUSIONS:Wide cross-national inequalities exist in workforce capacity and reimbursed care for people with RMDs. RheumaFacts delivers the first harmonised basis for monitoring these gaps, enabling EULAR and national societies to track progress and inform health policy makers to advocate for improving the quality of life of people with RMDs.

Despite major scientific advances, delivering high-quality care for children with inflammatory rheumatic and musculoskeletal diseases remains challenging. The field of paediatric rheumatology lies at the intersection of different disciplines, and requires excellent highly specialised medical expertise based on rapidly deepening knowledge in rheumatology and immunology. At the same time, this field relies on compassionate paediatricians understanding the needs of developing children as a vulnerable population. Training pathways and professional recognition vary widely between countries, and formal subspecialty accreditation is available inconsistently. Based on a Europe-wide expert survey, this Viewpoint examines why paediatric rheumatology is still not universally recognised as a distinct subspecialty and how insufficient access to formal accreditation leads to fragmented representation and low visibility of this discipline. We argue that stronger international advocacy involving patients and families is urgently required to support the sustainable development of the field and to ensure equitable, evidence-based, developmentally and psychologically appropriate care for all affected children.

OBJECTIVE:This prospective study assesses the response to canakinumab monotherapy administered as three monthly subcutaneous injections in glucocorticoid-naïve patients with newly diagnosed systemic juvenile idiopathic arthritis (sJIA) and Still disease and evaluates the durability of drug-free inactive disease for up to nine months after canakinumab cessation. METHODS:In a multicenter, two-phase open-label study of newly diagnosed sJIA or Still disease, canakinumab was administered at 4 mg/kg subcutaneously every 4 weeks for 12 weeks. Thereafter, patients were followed for an additional 40 weeks. Routine care was provided to nonresponders. RESULTS:In total, 21 patients were recruited, and 1 was excluded due to protocol violations. Fever resolved immediately in 17/19 patients. Two nonresponders (n = 2) were managed with different strategies: one received steroids alone, and the other received steroids plus canakinumab as part of routine care. By week 12, 14 patients achieved inactive disease. Thereafter, two flares occurred at weeks 24 and 36. Macrophage activation syndrome (MAS) was diagnosed in a third patient at week 19 and responded to treatment with glucocorticoids and cyclosporine A. By week 52, 11 patients had reached drug-free inactive disease and 3 had minimal disease activity. A total of 97 adverse events were reported; four were serious (one MAS, two disease flares, and one viral infection), but none were attributed to the study drug. CONCLUSION:Canakinumab steroid-free first-line therapy in newly diagnosed sJIA induces long-lasting, drug-free inactive disease in a substantial proportion of patients. Discontinuation of canakinumab was associated with disease flares in a minority of patients.

BackgroundProtein biomarkers such as interleukin 18 (IL-18), CXCL9, and the S100A alarmin proteins are increasingly used in the diagnosis and treatment of juvenile idiopathic arthritis (JIA) and Still's Disease (SD). Reported values for these biomarkers vary considerably among different testing platforms at different centers, representing a barrier to their clinical application as well as international research collaborations. We undertook a systematic evaluation of measurement comparability across different platforms in Europe (EU) and North America (NoA).MethodsRecombinant proteins including IL-18, CXCL9, S100A8/9, and S100A12 spiked into donor human serum were distributed in blinded fashion to participating centers in NoA and EU for determination of sample concentration on each center's measurement platform. Assay-specific mathematical correction formulas were calculated based on spike recovery data. Next, samples from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) First-line Options for Systemic JIA Treatment (FROST) study were utilized for validation on selected platforms. Comparisons between measurement platforms before and after mathematical correction were analyzed.ResultsIn the spiked samples, while overall strong correlation was observed for IL-18 measurements across different platforms, the percent recovery revealed significant analytical variation ranging between approximately 50-400%. Similar variation in recovery was also observed for CXCL9, S100A8/9, and S100A12 across different measurement platforms. Analysis of real-world samples from the FROST study revealed strong correlation in IL-18 and CXCL9 values when comparing the same bead-based platforms at two different centers. Significant differences and systematic bias in measurement of FROST samples were uncovered when comparing ELISA or Ella platforms to commercial Luminex platforms. The application of regression-based mathematical correction factors generated from the spike recovery assays could only partly resolve these inter-platform differences.ConclusionsThis is the first systematic analysis of the comparability of biomarker measurements used in JIA and SD across different platforms including ELISA, Luminex, and Ella. We demonstrate substantial differences in the quantification of standardized biomarker concentrations both between assay types and across testing sites. In contrast, analyses of real-world samples from sJIA patients showed high concordance between two independent Ella platforms, indicating that this platform could improve clinical and research standardization.

OBJECTIVE:To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice. METHODS:A systematic literature search was performed in both EMBASE and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure. RESULTS:Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatological conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported Janus kinase inhibitor in MAS. CONCLUSION:High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, the global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.

OBJECTIVE:Kawasaki disease (KD) is an acute systemic vasculitis predominantly affecting coronary arteries of infants and children. We recently identified leucin-rich α-2-glycoprotein 1 (LRG-1) as known transforming growth factor β1 (TGFβ1) signal-modulating molecule, orchestrating endothelial activation and cardiac remodeling, as associated with interleukin-1β (IL-1β) signaling in KD. In the present study, we aimed to assess the role for LRG-1 as part of a multimediator inflammatory environment as a possible direct mediator of human coronary artery endothelial activation. METHODS:Human coronary artery endothelial cells (HCAECs) were treated with a blood inflammatory matrix, with or without targeted inhibition of several inflammatory mediators, including LRG-1, and were analyzed for inflammatory activation or endothelial-to-mesenchymal transition (EndMT) on gene expression level. Proteomic profiling of the inflammatory matrix, treatment-naïve KD (n = 11), or healthy control serum samples (n = 10) was performed by proximity extension assay (n = 184 markers) and Luminex. RESULTS:Proteomic analysis of KD serum samples and the inflammatory matrix revealed elevation of 37 versus 50 inflammatory proteins, respectively, with 19 significantly up-regulated markers shared. The HCAEC culture with the inflammatory matrix resulted in inflammatory endothelial activation, which was most efficiently abrogated by IL-1 receptor type 1 (IL-1R1) inhibition compared to all other tested drugs. Whereas inflammatory endothelial activation can also link to TGFβ-driven EndMT, which was supported by respective signatures in our KD serum proteomics, we observed that in vitro inflammatory matrix-induced EndMT was partly impaired by both IL-1R1 and tumor necrosis factor inhibition compared to other tested drugs. CONCLUSIONS:Collectively, our observations in the context of a multimediator inflammatory environment indicate a prominent role of a specific clinically relevant cytokine signaling axis in inflammatory coronary artery endothelial activation and EndMT in the context of KD.

OBJECTIVE:We aimed to study the disease course, outcomes, and predictors of outcome in pediatric-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affecting the kidneys. METHODS:Patients eligible for this study had a diagnosis of granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or ANCA-positive pauci-immune glomerulonephritis, were 18 years or younger at diagnosis, had renal disease defined by biopsy or dialysis dependence, and had clinical data at diagnosis and at either 12 or 24 months. Ambispective data from A Registry for Children with Vasculitis/Pediatric Vasculitis Initiative Registry was used. The primary outcome was inactive renal disease (pediatric vasculitis activity score = 0 or 1) at 12 months. Secondary outcomes included rates of improved renal function and damage within 24 months. Renal function, defined by estimated glomerular filtration rate, was categorized into Kidney Disease Improving Global Outcomes (KDIGO) stages at diagnosis and tested as a predictor of outcome using a proportional-odds logistic regression model. RESULTS:A total of 145 patients were included: 68% were female, and 78% had GPA. At 12 months, 83% of patients achieved inactive renal disease; however, 42% had evidence of permanent renal damage. Compared with patients with normal renal function at diagnosis, patients with moderate to severely reduced renal function, or kidney failure at diagnosis, had an odds ratio of 8.62 (P = 0.002; 95% confidence interval [CI] 2.31-32.1) and 26.3 (P < 0.001; 95% CI 6.32-109), respectively, for being in a non-normal KDIGO category at 12 months. CONCLUSION:The majority of patients with pediatric AAV achieve inactive renal disease by 12 months; however, almost half have evidence of damage. Renal function at diagnosis is a strong predictor of renal function at 12 months.

Many studies analyze tissue-resident or blood-borne leukocytes to monitor disease progression. We hypothesized that the microvasculature serves as a distinct site for immune cell activity. Here, we investigate microvascular leukocyte phenotypes before, during and after acute kidney injury (AKI) in mice, uncovering unique characteristics in the kidney, liver, and lung. Using single-cell sequencing, we identify several immune cells that were up to 100-fold expanded in the kidney vasculature, including macrophages, dendritic cells (DC), and B cells. Regeneration after AKI is characterized by sustained remodeling of the renal microvascular interface. Homeostatic microvascular C1q+ macrophages withdraw from the vascular barrier which is subsequently repopulated by new subsets, including CD11c+F480+ and CD11c+F480- cells. These newly arrived macrophages exhibit enhanced phagocytic activity toward circulating bacteria and secretion of tumor necrosis factor, pointing to maladaptive repair mechanisms after AKI. These data suggest organ- and disease-specific microvascular immune dynamics which are not detectable through conventional blood and tissue analysis.

Juvenile idiopathic arthritis-associated uveitis (JIAU) typically takes a chronic course, frequently leading to ocular complications and often requiring long-term treatment. The present study assesses the 5-years outcome of JIAU by analyzing data from a prospective study initiated in 2010. Data from 75 patients with onset of uveitis after study enrollment, and with a documentation at 5-years follow-up (5yFU) were available for analysis of uveitis characteristics, frequency and predictors of „inactivity on medication “ (defined as inactive uveitis for ≥ 6 months) and „inactivity off medication “ (defined as inactive uveitis for ≥ 6 months off medication). At the 5yFU, visual acuity remained good in the majority of eyes (LogMAR < 0.1 in 65.5