scholarly journals Application of systems biology-based in silico tools to optimize treatment strategy identification in Still’s disease

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Cristina Segú-Vergés ◽  
Mireia Coma ◽  
Christoph Kessel ◽  
Serge Smeets ◽  
Dirk Foell ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Systems Biology ◽  
Treatment Strategy ◽  
In Silico ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Treat To Target ◽  
Molecular Characteristics ◽  
Expression Data ◽  
Still’S Disease ◽  
Still's Disease

Abstract Background Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) are manifestations of an autoinflammatory disorder with complex pathophysiology and significant morbidity, together also termed Still’s disease. The objective of the current study is to set in silico models based on systems biology and investigate the optimal treat-to-target strategy for Still’s disease as a proof-of-concept of the modeling approach. Methods Molecular characteristics of Still’s disease and data on biological inhibitors of interleukin (IL)-1 (anakinra, canakinumab), IL-6 (tocilizumab, sarilumab), and glucocorticoids as well as conventional disease-modifying anti-rheumatic drugs (DMARDs, methotrexate) were used to construct in silico mechanisms of action (MoA) models by means of Therapeutic Performance Mapping System (TPMS) technology. TPMS combines artificial neuronal networks, sampling-based methods, and artificial intelligence. Model outcomes were validated with published expression data from sJIA patients. Results Biologicals demonstrated more pathophysiology-directed efficiency than non-biological drugs. IL-1 blockade mainly acts on proteins implicated in the innate immune system, while IL-6 signaling blockade has a weaker effect on innate immunity and rather affects adaptive immune mechanisms. The MoA models showed that in the autoinflammatory/systemic phases of Still’s disease, in which the innate immunity plays a pivotal role, the IL-1β-neutralizing antibody canakinumab is more efficient than the IL-6 receptor-inhibiting antibody tocilizumab. MoA models reproduced 67% of the information obtained from expression data. Conclusions Systems biology-based modeling supported the preferred use of biologics as an immunomodulatory treatment strategy for Still’s disease. Our results reinforce the role for IL-1 blockade on innate immunity regulation, which is critical in systemic autoinflammatory diseases. This further encourages early use on Still’s disease IL-1 blockade to prevent the development of disease or drug-related complications. Further analysis at the clinical level will validate the findings and help determining the timeframe of the window of opportunity for canakinumab treatment.

scholarly journals Adult Still's disease: New horizons

2021 ◽  
Vol 59 (6) ◽  
pp. 645-665
Author(s):  
E. L. Nasonov ◽  
E. Feist
Keyword(s):  
Innate Immunity ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Unknown Etiology ◽  
Still’S Disease ◽  
New Horizons ◽  
Still's Disease ◽  
Adult Still's Disease ◽  
Laboratory Biomarkers ◽  
Genetically Determined ◽  
Pro Inflammatory Cytokines

Still's disease in children (systemic juvenile idiopathic arthritis - JIA) and adult Still's disease (ASD) are considered as systemic autoinflammatory diseases of unknown etiology, which are based on similar immunopathogenetic mechanisms associated with genetically determined disorders of the mechanisms of innate immunity. ASD was first described 50 years ago by the English rheumatologist Eric George Lapthorne Bywaters. The molecular basis of ASD immunopathogenesis is the activation of innate immunity associated with NLRP3 inflammasome-dependent mechanisms of inflammation, characterized by the overproduction of “pro-inflammatory” cytokines - interleukin (IL) 1 and IL-18, inducing the synthesis of other proinflammatory inflammatory mediators. A review of new data concerning the mechanisms of immunopathology, clinical polymorphism, laboratory biomarkers and the possibilities of ASD pharmacotherapy is presented.Particular attention is paid to the prospects for the use of monoclonal antibodies to IL-1β - canakinumab. The problems associated with the generality of clinical and laboratory disorders, pathogenetic mechanisms and pharmacotherapy of ASD and coronavirus disease 2019 (COVID-19) are considered.

scholarly journals The Role of Interleukin 18/Interleukin 18-Binding Protein in Adult-Onset Still’s Disease and Systemic Juvenile Idiopathic Arthritis

2022 ◽  
Vol 11 (2) ◽  
pp. 430
Author(s):  
Charlotte Girard-Guyonvarc’h ◽  
Mathilde Harel ◽  
Cem Gabay
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Binding Protein ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Free Form ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Interleukin 18 ◽  
Still's Disease ◽  
Adult Onset Still's Disease

Interleukin 18 (IL-18) is a pro-inflammatory cytokine of the IL-1 family, whose activity is tightly controlled at the level of production, as well as signalization. Notably, it is buffered by its natural inhibitor, IL-18 binding protein (IL-18BP), which is massively present in circulation in normal and in most pathological conditions, thus preventing harmful pro-inflammatory systemic effects of IL-18. IL-18 has long been considered to be involved in the pathophysiology of various inflammatory diseases. However, a first clinical trial using recombinant IL-18BP for the treatment of rheumatoid arthritis and psoriasis gave disappointing results. Direct measurements of unbound, bioactive, free form of circulating IL-18 demonstrated that IL-18 was more specifically involved in adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) but also in their most severe complication, macrophage activation syndrome (MAS). More importantly, administration of recombinant IL-18BP to patients with AOSD, and sJIA with MAS, showed promising results. This review summarizes available data regarding IL-18 and IL-18BP in AOSD and sJIA in mouse models and humans and shows the importance of IL-18/IL-18BP imbalance in these conditions, leading to the conclusion that IL-18, particularly free IL-18, may be a useful biomarker in these diseases and an interesting therapeutic target.

scholarly journals Management of adult-onset Still’s disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Serena Colafrancesco ◽  
◽  
Maria Manara ◽  
Alessandra Bortoluzzi ◽  
Teodora Serban ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Delphi Process ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Biologic Treatment ◽  
Still's Disease ◽  
Late Treatment ◽  
Adult Onset Still's Disease

Abstract Background Adult-onset Still’s disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently small and often uncontrolled. Our objective was to develop recommendations for the use of interleukin (IL)-1 inhibitors in the management of patients with AOSD, based on the best evidence and expert opinion. Methods A panel of 10 experts (9 rheumatologists and 1 pediatrician) was established. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed on the MEDLINE (Pubmed), EMBASE, and BIOSIS databases through April 2018 to identify (1) differences and similarities between AOSD and pediatric Still’s disease (systemic juvenile idiopathic arthritis [SJIA]) and (2) the efficacy and safety of IL-1 inhibitors in AOSD treatment. In the second step, the statements were submitted in a Delphi process to a panel of 67 rheumatologists. Consensus threshold was set at 66%: positive, > 66% of voters selected scores 3 to 5; negative, > 66% of voters selected scores 1 or 2. In the third step, the voting results were analyzed, and the statements were finalized. Results Eleven statements were developed. Forty-six of 67 rheumatologists (72%) participated in the Delphi process. A positive consensus was reached after the first round of voting and was full (> 95%) on the majority of statements. A large consensus was achieved in considering AOSD and SJIA as the same disease. The use of anti-IL-1 therapies in refractory patients was considered quite safe and effective both as the first and as a subsequent line of biologic treatment, especially in systemic patients. Because of the lack of head-to-head comparisons, a different profile of efficacy among IL-1 inhibitors could not be established. There was a large consensus that failure of the first IL-1 inhibitor does not preclude response to another one. The lack of studies comparing early versus late treatment did not allow to draw conclusions; however, data from SJIA suggest a better response in early treatment. Conclusions The Delphi method was used to develop recommendations that we hope will help clinicians in the management of patients with AOSD refractory to conventional therapies.

scholarly journals An Update on the Pathogenic Role of Neutrophils in Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 13038
Author(s):  
Ji-Won Kim ◽  
Mi-Hyun Ahn ◽  
Ju-Yang Jung ◽  
Chang-Hee Suh ◽  
Hyoun-Ah Kim
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Immune Defense ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Wide Range ◽  
Adult Onset Still's Disease

Neutrophils are innate immune phagocytes that play a key role in immune defense against invading pathogens. The main offensive mechanisms of neutrophils are the phagocytosis of pathogens, release of granules, and production of cytokines. The formation of neutrophil extracellular traps (NETs) has been described as a novel defense mechanism in the literature. NETs are a network of fibers assembled from chromatin deoxyribonucleic acid, histones, and neutrophil granule proteins that have the ability to kill pathogens, while they can also cause toxic effects in hosts. Activated neutrophils with NET formation stimulate autoimmune responses related to a wide range of inflammatory autoimmune diseases by exposing autoantigens in susceptible individuals. The association between increased NET formation and autoimmunity was first reported in antineutrophil cytoplasmic antibody-related vasculitis, and the role of NETs in various diseases, including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, has since been elucidated in research. Herein, we discuss the mechanistic role of neutrophils, including NETs, in the pathogenesis of systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still’s disease (AOSD), and provide their clinical values as biomarkers for monitoring and prognosis.

Serum S100A8/A9, But Not Follistatin-like Protein 1 and Interleukin 18, May Be a Useful Biomarker of Disease Activity in Adult-onset Still’s Disease

2012 ◽  
Vol 39 (7) ◽  
pp. 1399-1406 ◽  
Author(s):  
HYOUN-AH KIM ◽  
JEONG-MI AN ◽  
JIN-YOUNG NAM ◽  
JA-YOUNG JEON ◽  
CHANG-HEE SUH
Keyword(s):  
Disease Activity ◽  
Systemic Disease ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Disease Score ◽  
Still’S Disease ◽  
Interleukin 18 ◽  
Still's Disease ◽  
Adult Onset Still's Disease

Objective.S100A8/A9, follistatin-like protein 1, and interleukin 18 (IL-18) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis or adult-onset Still’s disease (AOSD). We investigated the clinical significance of these factors in AOSD.Methods.Blood samples were collected from 36 patients with AOSD, 40 patients with rheumatoid arthritis (RA), and 33 healthy controls. Of the patients with AOSD, followup samples were collected from 16 patients after resolution of disease activity.Results.Serum levels of S100A8/A9 (11.77 ± 8.84 μg/ml) in AOSD patients were higher than those in RA patients (3.53 ± 3.43 μg/ml; p < 0.001) and controls (2.49 ± 1.83 μg/ml; p < 0.001). Follistatin-like protein 1 levels in AOSD were not different from those in RA and controls. IL-18 levels in AOSD (7560.3 ± 7577.6 pg/ml) were higher than those in RA (217.7 ± 292.1 pg/ml; p < 0.001) and controls (139.2 ± 86.2 pg/ml; p < 0.001). The sensitivity and specificity of IL-18 for diagnosing AOSD was highest with a cutoff value of 366.1 pg/ml. Serum S100A8/A9 correlated with leukocyte count, erythrocyte sedimentation rate, C-reactive protein, ferritin, and systemic disease score; however, IL-18 correlated only with ferritin and systemic disease score. S100A8/A9 was decreased after disease activity was resolved in followup of AOSD patients (9.96 ± 7.35 μg/ml in active AOSD vs 3.6 ± 4.77 μg/ml in resolved cases; p = 0.001). The change of S100A8/A9 was well correlated with that of systemic disease score.Conclusion.The data suggest that serum S100A8/A9 may be a useful biomarker for evaluating disease activity in patients with AOSD.

scholarly journals Anakinra in children and adults with Still’s disease

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_6) ◽  
pp. vi9-vi22 ◽  
Author(s):  
Sebastiaan J Vastert ◽  
Yvan Jamilloux ◽  
Pierre Quartier ◽  
Sven Ohlman ◽  
Lisa Osterling Koskinen ◽  
...  
Keyword(s):  
Systemic Juvenile Idiopathic Arthritis ◽  
Current Data ◽  
Inactive Disease ◽  
European Medicines Agency ◽  
Efficacy And Safety ◽  
Still’S Disease ◽  
First Line ◽  
Autoinflammatory Disorders ◽  
Common Features ◽  
Still's Disease

Abstract Systemic juvenile idiopathic arthritis and adult-onset Still’s disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease—Still’s disease—with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still’s disease. In this review we discuss the reasoning for considering Still’s disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still’s disease was remarkable, with clinically inactive disease or the equivalent reported for 23–100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still’s disease since it improves clinical outcome, especially if initiated early in the disease course.

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