Grant S. Schulert

Objective: The extent of uveitis risk in juvenile idiopathic arthritis (JIA) is based on clinical factors. We aim to compare the trajectories of tear‐based biomarker levels of patients with JIA with and without uveitis. Methods: This prospective multicenter study included children with JIA at risk for uveitis (JIA‐no‐U) and those with JIA‐associated uveitis (JIA‐U). Serial tear samples were collected from each eye by Schirmer strips at enrollment and the first and second follow‐up visits (FU1 and FU2). S100 proteins, cytokines, and chemokines were assayed by Luminex or enzyme‐linked immunosorbent assay and compared between groups. Results: Fifty patients (37 JIA‐no‐U, 13 JIA‐U) contributed 222 samples (150 JIA‐no‐U, 73 JIA‐U). At enrollment, there were no significant differences in biomarker levels between JIA‐U and JIA‐no‐U. During follow‐up of patients with JIA‐U, monocyte chemoattractant protein 1 (MCP‐1) levels increased longitudinally from enrollment to FU1 and FU2 (LS mean ± SE 1.63 ± 0.31 to 2.46 ± 0.31, P = 0.005; and 2.89 ± 0.32, P < 0.0001), and there was a similar increase in CXCL10 (LS mean ± SE 4.39 ± 0.41 to 5.26 ± 0.41, P = 0.030; and 6.51 ± 0.43, P < 0.0001) and interleukin‐8 (IL‐8) levels from enrollment to FU1 and FU2 (LS mean ± SE 3.09 ± 0.30 to 4.25 ± 0.30, P = 0.006; and 4.65 ± 0.32, P ≤ 0.001). In both groups, S100A12 and S100A8/A9 levels increased from enrollment to follow‐up. Conclusion: Longitudinal changes in MCP‐1, CXCL10, and IL‐8 levels in tear fluid in JIA‐U may reflect inflammatory ocular processes and support the role of monocytes and interferon‐related pathways in uveitis. Lack of differences in S100 proteins may reflect systemic inflammation from arthritis. Tear‐based biomarkers may support clinical factors for identifying children with JIA who develop uveitis.

Objective: Systemic juvenile idiopathic arthritis and adult‐onset Still disease represent a spectrum of Still disease characterized by dysregulated innate immunity, severe systemic inflammation, and risk of life‐threatening complications including macrophage activation syndrome (MAS) and associated lung disease (LD). Although interleukin‐1 (IL‐1) and IL‐6 pathway inhibitors have improved outcomes, a subset of patients develop severe, refractory disease. This article summarizes the current evidence and multidisciplinary expert perspectives on the role of allogeneic hematopoietic cell transplantation (HCT) in refractory Still disease. Methods: This Special Article is a conference summary based on presentations and multidisciplinary discussion at the 2024 Systemic Juvenile Idiopathic Arthritis Foundation NextGen Conference, which convened an international, multidisciplinary group of rheumatologists, transplant physicians, immunologists, pulmonologists, and patient advocates. Results: Recurrent MAS, progressive LD, persistent systemic inflammation despite IL‐1/IL‐6/JAK inhibition, and glucocorticoid dependence were identified as clinical features that may warrant consideration of allogeneic HCT in Still disease. Available data, mainly from small pediatric cohorts, suggest that allogeneic HCT can achieve clinical remission and improve pulmonary outcomes in select patients. However, transplant‐related mortality remains substantial, particularly in patients with LD, and inflammatory disease may recur after HCT. HCT data in adults remain limited. Conclusion: Allogeneic HCT may be considered for select patients with severe, refractory Still disease, particularly those with recurrent MAS and/or progressive LD. Early multidisciplinary evaluation, shared decision‐making, and careful patient selection are essential. Prospective multicenter studies and closer collaboration between pediatric and adult providers are needed to refine patient selection and improve outcomes.

Objective: Macrophage activation syndrome (MAS) is a rare, life‐threatening hyperinflammatory condition that complicates rheumatologic diseases, most commonly Still disease. Despite increasing awareness and emerging recommendations, MAS treatment remains heterogeneous worldwide. The METAPHOR project aimed to describe real‐life therapeutic strategies for MAS, exploring differences across underlying diseases, geographic regions, physician subspecialties, and drug availability. Methods: An international web‐based survey was developed by a multidisciplinary expert panel together with a patient representative following a systematic literature review. The survey was anonymously completed through Paediatric Rheumatology European Society/Paediatric Rheumatology International Trial Organisation and the Histiocyte Society networks (October to December 2023). Treatment strategies for MAS across different rheumatologic contexts were explored. Responses were analyzed descriptively and stratified by geography, subspecialty, clinical experience, and underlying disease. Results: A total of 287 physicians from 64 countries completed the survey, the majority being pediatric rheumatologists with more than five years of experience. Glucocorticoids, particularly intravenous methylprednisolone, were consistently identified as first‐line therapy across all MAS subtypes (for 44% of clinicians as monotherapy). Anakinra, ciclosporin, and intravenous Ig were the most frequently combined agents. However, their use varied markedly by underlying disease and geographic region, with anakinra preferentially used in Still disease–associated MAS. Striking global disparities in drug availability, particularly for anakinra and emapalumab, significantly influenced treatment choices and were associated with increased reliance on steroid monotherapy. Conclusion: MAS management remains highly heterogeneous worldwide. Although glucocorticoids remain foundational, reducing steroid reliance through equitable access to immunomodulatory therapies and advancing mechanism‐based strategies represent critical priorities in optimizing MAS care. image

Objective: Information is limited on the natural history and current treatment patterns in macrophage activation syndrome (MAS), a life‐threatening hyperinflammatory syndrome complicating Still's disease (systemic juvenile idiopathic arthritis [sJIA] and adult‐onset Still's disease [AOSD]). AMETHYST aimed to describe real‐world treatment patterns and outcomes in glucocorticoid (GC)–refractory MAS complicating Still's disease. Methods: In this retrospective cohort study, medical data from January 1, 2012, to March 31, 2023, were abstracted from charts of all eligible patients across eight sites in Europe, Canada, and the United States for index MAS episodes (occurring between January 1, 2012, and September 30, 2022, and meeting eligibility criteria). Results: Overall, 55 of 64 included patients (86%) had sJIA and 9 of 64 (14%) had AOSD. Most patients (53/64 [82.8%]) were children at index (median age: 7.0 years). MAS was characterized by rash (60.4%), fever (52.8%), and hepatic involvement (49.1%). All patients received GCs; most were also treated with anakinra (48/64 [75%]) and/or ciclosporin (33/64 [51.6%]). Normalization of seven (complete MAS laboratory remission) or at least three (partial remission) prespecified laboratory parameters occurred in 7 of 64 (10.9%) and 41 of 64 patients (64.1%), respectively. GCs were tapered in 50 of 64 patients (78.1%) (median: 39.9 days). Per investigator assessment of clinical signs/symptoms for the index MAS episode, 24 of 64 (37.5%) and 26 of 64 patients (40.6%) had a complete and partial response, respectively. MAS recurred in 20 of 64 patients (31.3%). Seven of 64 patients (10.9%) died, and the estimated one‐year survival probability was 93.75%. Conclusions: Low MAS laboratory remission rates and toxicities of high‐dose GCs combined with other treatments highlight the need for safer, more effective therapies.

Juvenile idiopathic arthritis (JIA), the most common class of pediatric rheumatic diseases, can lead to joint damage and extra-articular features including uveitis. Early treatment can improve functional outcomes; but many patients do not respond to first-line treatments. We present a JIA Immunochip-based association analysis of rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. This study spans 3,939 cases and 14,412 controls, including 1,123 cases and 1,356 controls not previously analyzed. We identify 41 (14 novel) JIA risk regions and report a JIA polygenic risk score that also associates with age of onset. Functional mechanisms presented include: a novel interaction between HLA-A*02:01 and ERAP2 , cluster-based approach for functional amino acid discovery within HLA-DRB1, and sequence-dependent DNA topology for variant prioritization. We present a comprehensive list of curated gene-drug/small molecule interactions for clinically focused studies. These findings provide a deepened understanding of the genetics of JIA and potential mechanisms to inform precision medicine.

Lung disease associated with systemic juvenile idiopathic arthritis (SJIA-LD) remains poorly understood. Evaluation of bronchoalveolar lavage fluid (BALF)

Protein 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). Recombinant 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. In 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. This 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.

Juvenile dermatomyositis (JDM) is a chronic multisystem vasculopathy and inflammatory myopathy characterized by proximal muscle weakness, distinct rash, and risk of complications such as calcinosis cutis, skin ulceration, and mortality. Molecular insight from diagnostic muscle biopsy histology is limited, and the mechanistic pathoetiology of JDM remains poorly defined. We used single nuclei transcriptomics to assess muscle samples from patients with newly diagnosed treatment-naïve JDM. As a control, we assessed muscle samples from patients with congenital (nemaline) myopathy (CM), a non-inflammatory disorder. A total of 25,794 high quality nuclei were analyzed and clustered into various muscle-resident or infiltrating cellular populations. JDM tissue was characterized by an enriched interferon (IFN) response signature across endothelial, stromal, and immune cell compartments. Endothelial and perivascular populations showed increased inflammatory and angiogenic programs. Intercellular communication inference analysis identified dysregulated vascular endothelial growth factor (VEGF)-related signaling involving endothelial, stromal, and myonuclear populations as a possible mechanism for myonuclear-driven modulation of the muscle microvasculature. Spatial RNA in situ hybridization supported increased expression of selected IFN responsive and angiogenesis signaling genes in JDM tissue. Collectively, these data provide a cell type-resolved view of treatment-naïve JDM muscle and highlight vascular and IFN pathways for follow-up in larger cohorts.