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

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.

Effective Therapy of Tocilizumab on Systemic Juvenile Idiopathic Arthritis Associated Refractory Macrophage Activation Syndrome

Objectives To evaluate the safety and efficacy of tocilizumab (TCZ) on refractory macrophage activation syndrome (rMAS) associated with systemic juvenile idiopathic arthritis (sJIA-rMAS). Methods We retrospectively reviewed the charts of 14 patients diagnosed with sJIA-rMAS, who were treated with TCZ after failing conventional therapies at three hospital centers from Jan 2016 to Dec 2020. Demographic, clinical, and laboratory characteristics were recorded at the onset of MAS, before TCZ (pre-TCZ) and 14 days after TCZ (post-TCZ). Results The clinical manifestation of sJIA-rMAS included fever (100%), skin rashes (35.7%), lymphadenomegaly (42.9%), hepatomegaly (57.1%), splenomegaly (7.1%), gastrointestinal symptoms (28.6%), arthritis (14.3%), myalgia (28.6%) and polyserositis (14.3%). After TCZ treatment, fever (100%, 14/14), gastrointestinal symptoms (100%, 4/4) and myalgia (100%, 4/4) were significantly improved after one week (p< 0.05). Skin rashes, lymphadenomegaly and arthritis also improved in many patients but these parameters did not reach statistical significance. In post-TCZ group, decreases in levels of c-reactive protein, erythrocyte sedimentation rate and serum ferritin of sJIA-rMAS were observed compared with pre-TCZ (p< 0.05). Although not statistically significant, post-TCZ group showed normalization of white blood cell, platelet count, alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase and triglyceride levels compared with pre-TCZ. No disease relapse or fatality was recorded during the follow-up (25 months, range 3–60 months). Conclusions TCZ is safe and effective for the treatment of sJIA-rMAS after failure of conventional therapies.

Adult Still's disease: New horizons

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.

Efficacy And Safety of Canakinumab As A Second-Line Biologic After Tocilizumab Treatment Failure in Children With Systemic Juvenile Idiopathic Arthritis: A Single-Center Cohort Study Using Routinely Collected Health Data

Background: A significant number of systemic juvenile idiopathic arthritis (sJIA) patients discontinue biologic disease-modifying antirheumatic drugs (DMARDs) due to lack of efficacy or safety concerns. Studies of biologic therapy switch regimens in sJIA are required.Methods: Patients with sJIA who switched from tocilizumab (due to lack of efficacy or safety) to canakinumab (4 mg/kg every 4 weeks) and were hospitalized at the rheumatology department from August 2012 to July 2020 were included. Primary efficacy outcomes were 30% or greater improvement based on the pediatric criteria of the American College of Rheumatology (ACR30), achievement of inactive disease (JADAS‑71 =0) and clinical remission (ACR sJIA clinical inactive disease criteria). Follow-up was 12 months or the closest time point (not less than 6 and not more than 18 months). Data were extracted from outpatient medical records.Results: During the study period, 46 patients with sJIA switched from tocilizumab to canakinumab. Median age at canakinumab initiation was 8.2 (interquartile range 4.0; 12.9) years, and median sJIA duration was 1.8 (0.8; 5.8) years; 37 (80%) patients received at least one non-biologic DMARD (oral corticosteroids, methotrexate and/or cyclosporine A). Study outcomes were followed up in 45 patients (one patient did not attend the follow-up for an unknown reason); median follow-up was 359 (282; 404) days. During the follow-up, canakinumab was discontinued in one patient (due to tuberculosis detection) and the dose was reduced or the injection interval increased in four (9%) patients. In total, 27 (60%) patients continued to receive at least one non-biologic DMARD. Improvement according to the ACR30 criteria was achieved in 43 patients (96%; 95% confidence interval, 85–99), inactive disease in 42 (93%; 82–98), and clinical remission in 37 (82%; 69‑91); after adjustment for actual time-at-risk, the rates were 83, 85 and 73 events per 100 person-years, respectively. During follow-up, 23 adverse events (most frequently infections) were reported in 19/45 (42%) patients; 5/45 (11%) patients developed macrophage activation syndrome, with a favorable outcome in all cases.Conclusions: Short-term (about 12 months) canakinumab therapy was found to be potentially effective as second-line biologic therapy after discontinuation of tocilizumab in patients with sJIA. Trial registration: CACZ885G2301E1 (G2301; NCT00891046 registered on April 29, 2009) and CACZ885G2306 (G2306; NCT02296424 registered on November 20, 2014).

Laboratory Examination in Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH) is derived from the word hemophagocytosis, in which macrophagesinfiltrate tissue extensively, and unspecifically phagocyte blood and bone marrow cells. The deviant activation of cytotoxicCD8+ T-cells causing the release of inflammatory cytokines is the core pathogenesis of HLH. Hemophagocyticlymphohistiocytosis is a regulatory disorder of the immune system, with clinical signs and symptoms of extremeinflammation and cytopenia, hepatitis, and severe and life-threatening central nervous system dysfunction. The name of theHLH disorder was recently proposed to be "Hyperinflammatory Lymphohistiocytosis" (also known as HLH). Enforcement ofHLH diagnosis by the Histiocyte Society based on HLH 2004 updated diagnostic criteria consists of five of the following eightdiagnostic criteria: fever, splenomegaly, cytopenia (two or more of three lineages in peripheral blood), hypertriglyceridemiaor hypofibrinogenemia, hyperferritinemia, hemophagocytes in the bone marrow/lien/lymph, the low or non-existentactivity of Natural Killer (NK) cells, increased sCD25. H-score, MH-score, and systemic Juvenile Idiopathic Arthritis(sJIA)/Macrophage Activated Syndrome (MAS) classification criteria are also used to enforce HLH diagnoses.Hemophagocytic lymphohistiocytosis is challenging to recognize and has a high mortality rate, especially in adults, rangingfrom 42 to 88%. Therefore, immediate diagnosis and therapy are essential. The introduction of HLH triggers is criticalbecause treatment is based on the underlying trigger. Cytokine storms due to Coronavirus Disease 19 (COVID-19) infectionhave significant similarities to the clinical and laboratory findings of HLH. Secondary HLH (sHLH) is suspected in severeCOVID-19 patients, so early diagnosis is potentially made based on the H-score.

Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis

Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision shaping cells that instruct other leukocytes to fine-tune innate and adaptive immune responses has come into view. Under homeostatic conditions, neutrophils are short-lived cells that are continuously released from the bone marrow. Their development starts with undifferentiated hematopoietic stem cells that pass through different immature subtypes to eventually become fully equipped, mature neutrophils capable of launching fast and robust immune responses. During severe (systemic) inflammation, there is an increased need for neutrophils. The hematopoietic system rapidly adapts to this increased demand by switching from steady-state blood cell production to emergency granulopoiesis. During emergency granulopoiesis, the de novo production of neutrophils by the bone marrow and at extramedullary sites is augmented, while additional mature neutrophils are rapidly released from the marginated pools. Although neutrophils are indispensable for host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation of neutrophil homeostasis is imperative. In this review, we discuss the kinetics of neutrophil ontogenesis in homeostatic conditions and during emergency myelopoiesis and provide an overview of the different molecular players involved in this regulation. We substantiate this review with the example of an autoinflammatory disease, i.e. systemic juvenile idiopathic arthritis.

An Update on the Pathogenic Role of Neutrophils in Systemic Juvenile Idiopathic Arthritis and 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.

Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single-center study

Background This study aimed to perform an immunoprofiling of systemic juvenile idiopathic arthritis (sJIA) in order to define biomarkers of clinical use as well as reveal new immune mechanisms. Methods Immunoprofiling of plasma samples from a clinically well-described cohort consisting of 21 sJIA patients as well as 60 age and sex matched healthy controls, was performed by a highly sensitive proteomic immunoassay. Based on the biomarkers being significantly up- or down-regulated in cross-sectional and paired analysis, related canonical pathways and cellular functions were explored by Ingenuity Pathway Analysis (IPA). Results The well-studied sJIA biomarkers, IL6, IL18 and S100A12, were confirmed to be increased during active sJIA as compared to healthy controls. IL18 was the only factor found to be increased during inactive sJIA as compared to healthy controls. Novel factors, including CASP8, CCL23, CD6, CXCL1, CXCL11, CXCL5, EIF4EBP1, KITLG, MMP1, OSM, SIRT2, SULT1A1 and TNFSF11, were found to be differentially expressed in active and/or inactive sJIA and healthy controls. No significant pathway activation could be predicted based on the limited factor input to the IPA. High Mobility Group Box 1 (HMGB1), a damage associated molecular pattern being involved in a series of inflammatory diseases, was determined to be higher in active sJIA than inactive sJIA. Conclusions We could identify a novel set of biomarkers distinguishing active sJIA from inactive sJIA or healthy controls. Our findings enable a better understanding of the immune mechanisms active in sJIA and aid the development of future diagnostic and therapeutic strategies.