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Since IL-18 has recently emerged as a biomarker associated with refractory disease course in SJIA, the focus of the discussion was the feasibility of the biomarker-driven drug development to SJIA. Overall, there was broad agreement on the conclusion that IL-18 is a uniquely specific biomarker for many of the subsets of SJIA most in need of new therapies, and it may define a class of diseases mediated by IL-18 excess. The consensus was that leveraging IL-18 remains our most promising "lead" for use in refractory SJIA as it may mechanistically explain the disease pathophysiology and lead to more targeted therapies. [ABSTRACT FROM AUTHOR]

The article discusses the proceedings of the 4th NextGen Therapies for SJIA and MAS virtual symposium, which aimed to identify barriers to clinical research and develop new strategies for refractory Systemic Juvenile Idiopathic Arthritis (SJIA) and Macrophage Activation Syndrome (MAS). SJIA is a severe subtype of chronic childhood arthropathy characterized by systemic immune activation, while MAS is a potentially fatal episode of systemic hyperinflammation. The symposium focused on the development of new therapies for SJIA-associated lung disease (SJIA-LD) and MAS, as well as alternative designs for clinical trials and the use of biomarkers for treatment response. The article also highlights the need for improved outcome measures that capture the systemic component of SJIA, particularly the lung disease. [Extracted from the article]

Systemic juvenile idiopathic arthritis associated with interstitial lung disease (SJIA-LD) represents a highly morbid subset of SJIA for which effective therapies are lacking. We report the case of a patient with refractory SJIA-LD who underwent treatment with MAS-825, an investigational bispecific monoclonal antibody targeting IL-1β and IL-18. MAS-825 treatment was associated with a marked reduction in total IL-18 and free IL-18 in both serum and bronchoalveolar lavage fluid (BAL). Baseline oxygen saturation, exercise tolerance, and quality of life metrics improved after treatment with MAS-825, while pulmonary function testing remained stable. Following treatment, the BAL showed no evidence of pulmonary alveolar proteinosis and inflammatory infiltrates were markedly reduced, reflected by decreased numbers of CD4 T-cells, CD8 T-cells, and macrophages. The patient was able to wean entirely off systemic corticosteroids and other biologics after 10 months of treatment with MAS-825 and experienced no side effects of the drug. This case demonstrates improvement in pulmonary symptoms, lung inflammation, and burden of immunomodulatory therapy after treatment with MAS-825 and suggests that simultaneous targeting of both IL-1β and IL-18 may be a safe and effective treatment strategy in SJIA-LD. [ABSTRACT FROM AUTHOR]

Objective: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high‐mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co‐occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA‐LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA‐LD. Methods: We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA‐LD, or other related diseases. We verified selected findings by enzyme‐linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA‐LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. Results: Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat‐shock proteins and glycolytic enzymes. Interleukin‐18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA‐LD. We also identified an MAS‐independent SJIA‐LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM‐5), matrix metalloproteinase 7 (MMP‐7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM‐5 and MMP‐7 in the lungs of patients with SJIA‐LD. The ability of ICAM‐5 to distinguish SJIA‐LD from systemic JIA/MAS was independently validated. Conclusion: Serum proteins support a systemic JIA–to‐MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA‐LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM‐5, could aid in early detection and management of SJIA‐LD. [ABSTRACT FROM AUTHOR]

For reasons poorly understood, and despite the availability of biological medications blocking IL-1 and IL-6 that have markedly improved overall disease control, children with Systemic Juvenile Idiopathic Arthritis (SJIA) are now increasingly diagnosed with life-threatening chronic complications, including hepatitis and lung disease (SJIA-LD). On October 3–4, 2019, a two-day meeting, NextGen Therapies for Systemic Juvenile Idiopathic Arthritis (SJIA) & macrophage activation syndrome (MAS) organized by the Systemic JIA Foundation (www.systemicjia.org/) in Washington, DC brought together scientists, clinicians, parents and FDA representatives with the objectives (1) to integrate clinical and research findings in MAS and SJIA-LD, and (2) to develop a shared understanding of this seemingly new pulmonary complication of SJIA. The current manuscript summarizes discussions and conclusions of the meeting. [ABSTRACT FROM AUTHOR]

Objective: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS.Methods: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis.Results: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes.Conclusions: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition. [ABSTRACT FROM AUTHOR]

Objectives Systemic juvenile idiopathic arthritis (sJIA) is a childhood arthritis with features of autoinflammation and high risk of macrophage activation syndrome (MAS). IL-18 has been shown to have key roles in sJIA and MAS. We aimed to examine IL-18 levels in sJIA in relation to disease activity and history of MAS and other disease biomarkers namely S100 proteins and CXCL9. Methods Total IL-18, CXCL9 and S100 proteins levels were determined in 40 sJIA patients, and IL-18 levels were compared between patients with regards to disease activity, history of MAS, and other biomarkers. Results Total IL-18 levels were significantly higher in patients with active sJIA (median 16 499 pg/ml; interquartile range (IQR) 4816–61 839), and remained persistently elevated even in the majority of patients with inactive disease (1164 pg/ml; IQR 587–3444). Patients with history of MAS had significantly higher IL-18 levels (13 380 pg/ml; IQR 4212–62 628) as compared with those without MAS history (956.5 pg/ml; IQR 276.3–4262.5). Total IL-18 performed well with area under the curve of 0.8145 and 0.84 in predicting disease activity and history of MAS, respectively. We observed moderate correlation between IL-18 and CXCL9 (R = 0.56), S100A8/A9 (R = 0.47) and S100A12 (R = 0.46). The correlation was stronger for ferritin (R = 0.74) and overall for those with active disease. Conclusion Total IL-18 levels were elevated in the majority of sJIA patients regardless of clinical features, but were higher in patients with active disease and history of MAS. Change in IL-18 may reflect increased disease activity or development of MAS. [ABSTRACT FROM AUTHOR]

The article describes the case of 6-year-old mixed race male diagnosed with systemic juvenile idiopathic arthritis (sJIA) complicated by recurrent macrophage activation syndrome (MAS) episodes at age 14 months. Topics covered include the medical history of the patient, patient outcome following treatment with interleukin-18 binding protein (IL-18BP) and the association of IL-18BP with the stabilization of disease course and reduced MAS severity.

Objective: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).Methods: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.Results: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.Conclusions: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed. [ABSTRACT FROM AUTHOR]

The article deals with efforts to define macrophage activation syndrome (MAS). It references the study "2016 Classification Criteria for MAS Complicating Systemic Juvenile Idiopathic Arthritis (JIA): A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative," by A. Ravelli et al., published within the issue. The study focused on defining MAS as a complication of systemic JIA.

Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed singlecell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications. [ABSTRACT FROM AUTHOR]