Scott W. Canna

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

Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors, often including an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction ( Il18 ^tg ), showed baseline NK-cytopenia and CTL activation resembling MAS-susceptible patients. NK transcriptomes reflected IL-18/IFNg-axis activation and cell cycle upregulation. LCMV infection of Il18 ^tg mice causes HLH/MAS without affecting viral control, but is not a significant NK challenge. Early after infection with NK-dependent mousepox, Il18 ^tg NKs failed to activate appropriately, but CTLs quickly hyperactivated and mousepox control remained intact. Mousepox-infected Il18 ^tg mice then developed signs of HLH/MAS including hepatosplenic necrosis. Their viral control was impaired, possibly because they failed to expand mousepox-specific CTLs. Il18bp ^KO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18 ^tg mice partially rescued virus-specific CTL responses, viral control, and survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.

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.

Background: Monogenic autoinflammatory disorders arise from genetic defects that pathologically activate innate immunity. IRAK4, a serine/threonine kinase in the Myddosome pathway, mediates IL-1 and Toll-like receptor signaling, driving proinflammatory cytokine and type I interferon responses. While biallelic loss-of-function IRAK4 variants cause an immunodeficiency, recent reports implicate biallelic IRAK4 variants in severe neuro- and systemic autoinflammation (NASA). We investigated a child with a similar phenotype and screened unsolved autoinflammatory leukoencephalopathies in the Myelin Disorders Biorepository Project (MDBP). Methods: Individuals with unexplained autoinflammatory leukoencephalopathy and no unifying molecular diagnosis were identified in the Myelin Disorders Biorepository Project (MDBP), and genome sequencing was reanalyzed to prioritize rare, protein-altering and splice-affecting variants. Candidate variants and their splicing consequences were interrogated with short-read and targeted long-read RNA sequencing, benchmarked against control PBMC and normal-tissue transcriptomes. Nonsense mediated decay of transcripts was also assessed. Clinical, genetic, and treatment data were extracted by standardized deep phenotyping, and brain MRI was reviewed in consensus by two pediatric neuroradiologists. Results: We identified six patients from five unrelated families with biallelic, rare IRAK4 variants presenting with severe, persistent autoinflammation without immunodeficiency. Variants included two homozygous and three compound heterozygous changes. All patients had a concordant clinical and radiologic syndrome: episodic, waxing–waning encephalopathy with refractory seizures; neuroimaging showed transient white matter edema that evolved to gliosis, superimposed on marked calcifications and ensuing cerebral atrophy. Biomarkers indicated neuroinflammation and anemia in all cases. Median age at neurologic symptom onset was 12.96 years (IQR 9.44). Immune-suppressive therapies achieved partial benefit, but most patients had ongoing seizures, persistent neuroinflammation, and progressive disease, and without treatment, loss of life. Conclusion: In these six patients, a strongly concordant clinical and radiological phenotype emerges of IRAK4 - mediated autoinflammation, expanding the phenotypic and mutational spectrum of IRAK4 -related disease. Further studies are needed to define mechanisms and optimal treatments.

Caring for children with complex immune disorders is part of the heritage of pediatric rheumatology that extends back to the original founders of the field. Over the past 50 years, pediatric rheumatologists have been central to advancing discovery and pioneering innovative treatment approaches for pediatric patients with multifaceted immune dysfunction. This includes dissecting disease mechanisms and identifying novel genes associated with inflammasome activation, IL‐18 opathies, type I interferonopathies, monogenic mosaic disorders, and other forms of immune dysregulation. Pediatric rheumatologists have made foundational contributions to the management of patients with these conditions by leveraging their expertise in existing immunomodulatory medications and recognizing new drug targets. In the next 50 years, scientists and clinicians in the field are poised to make substantial innovations in understanding the causes and biomarkers of immune dysregulation. By harnessing the power of precision medicine, cellular therapies, and immune multidisciplinary teams, pediatric rheumatologists will continue to drive discoveries that will improve outcomes for patients with immune dysregulation.

Gain-of-function (GOF) variants in STAT3 cause a complex disorder characterized by early-onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8 ⁺ T cells have been implicated as pathogenic drivers of autoimmunity, though the exact mechanisms remain poorly understood. Here, we found that in patients with STAT3 GOF, CD8 ⁺ T cells exist in an activated state. Functional assessment revealed that naive CD8 ⁺ T cells have an increased capacity for IFN-γ and TNF-α production, with type I and type II IFN transcriptional signatures. Evaluation of immunoregulatory pathways revealed dysregulation of the purinergic signaling axis in CD8 ⁺ T cells: CD39 was increased, whereas downstream purinergic family members, CD73 and the adenosine receptor A _2A R, were downregulated, impairing the potential to produce or sense immunosuppressive adenosine. Evaluation of the impact of precision therapy, in the form of JAK inhibition, at a cellular and functional level revealed partial normalization of CD8 ⁺ T cell dysregulation in patients, including aberrant cytokine production. Our study suggests that a dysregulated purinergic signaling axis plays a key role in CD8 ⁺ T cell dysregulation in STAT3 GOF and may have implications for other rare monogenic immune disorders and common inflammatory disorders.

Objective: The physician global assessment of lung disease (PGALD) is a recently proposed disease activity measure for patients with systemic juvenile idiopathic arthritis–associated lung disease (SJIA‐LD). This study evaluates the reliability and construct validity of the PGALD. Methods: Fifty‐seven pediatric rheumatologists and pulmonologists with experience caring for children with SJIA‐LD were invited to rate 20 clinical vignettes using the PGALD, a 10‐point Likert scale (0 = inactive SJIA‐LD; 10 = highly active SJIA‐LD). Raters were also asked to rate a subset of eight repeat vignettes. Interrater and intrarater reliability were assessed using intraclass correlation coefficients (ICCs), whereas SJIA‐LD features influencing PGALD ratings were assessed using univariate analysis. Results: The ICC for all raters was 0.68 (95% confidence interval [CI] 0.54–0.82), indicating moderate to good interrater reliability. The retest ICC was 0.86 (95% CI 0.82–0.89), indicating good intrarater reliability. Factors associated with higher mean PGALD scores included the presence of crackles on auscultation (5.7 vs 2.9; P = 0.001), hypoxemia on pulse oximeter (5.6 vs 3.2; P = 0.01), current oxygen requirement (6.3 vs 3.5; P = 0.04), suggestive diagnostic imaging features ( P ≤ 0.01), and three or more prescribed medications for SJIA‐LD ( P ≤ 0.01). Pulmonary function measures demonstrated significant negative correlations with PGALD scores: forced vital capacity (r = −0.71; P = 0.01), total lung capacity (r = −0.92; P = 0.01), and lung diffusion capacity (r = −0.97; P = 0.0002). Only C‐reactive protein was weakly to moderately correlated with PGALD scores (r = 0.39; P = 0.09), whereas other laboratory markers (ferritin, interleukin 18, CXCL9, and sIL‐2R) were not significantly correlated. Conclusions: The PGALD is a novel measure of SJIA‐LD activity. Its initial validation suggests acceptable construct validity and reliability. Additional studies are needed to assess its responsiveness to change over time.

Objectives: Chronic lung disease is a potentially life‐threatening complication of systemic juvenile idiopathic arthritis (SJIA‐LD). However, its natural history, etiology, and effective management are unclear. We aimed to describe the baseline characteristics and biomarker profiles of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry SJIA‐LD cohort. Methods: Baseline data from all CARRA Registry patients with SJIA and those with SJIA‐LD were included and analyzed. Lung disease–specific data were obtained using a standardized case report form through REDCap Cloud. Plasma biomarker profiles were determined using a custom Luminex panel. Results: A total of 37 patients with SJIA‐LD from 16 CARRA sites were identified and compared to all 928 patients with SJIA without known LD in the CARRA Registry. Patients with SJIA‐LD were significantly younger at disease onset and were more likely to be of Asian descent. A higher medication burden was also found. Patients with SJIA‐LD had higher levels of multiple lung injury biomarkers, cytokines, and chemokines compared to patients with both active and inactive SJIA without LD and healthy controls. Cluster analysis proposed three groups of SJIA‐LD patients with distinct biomarker patterns reflecting differences in proinflammatory cytokines, type II chemokines, and markers of macrophage activation syndrome (MAS). Conclusions: The CARRA SJIA‐LD Cohort exhibits distinct clinical features, higher medication burden, frequent MAS, and plasma biomarker patterns specific to SJIA‐LD compared to patients with SJIA without LD. A study is ongoing to assess more detailed clinical features, disease progression, patient‐reported outcomes, and associated immune biomarkers.