Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies.

Purpose: A causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING-associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling.

Benefits of a Juvenile Arthritis Support Program (JASP-1) for children recently diagnosed with Juvenile Idiopathic Arthritis and their parents.

Background: Medical treatment for children with Juvenile Idiopathic Arthritis (JIA) has improved radically since the development of biological disease-modifying antirheumatic drugs. However, children suffer from pain and anxiety, and parents often experience loneliness and lack of support. Some parents reported that information provided at the time their child was diagnosed could be difficult to assimilate.

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).

Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome.

Background: Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein released extracellularly during proinflammatory lytic cell death or secreted by activated macrophages, NK cells, and additional cell types during infection or sterile injury. Extracellular HMGB1 orchestrates central events in inflammation as a prototype alarmin.

Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open-Label, Randomized Study.

Objective: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA).

Methods: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate.

Juvenile idiopathic arthritis and risk of cancer before and after the introduction of biological therapies.

Background: The risk of cancer, including any secular trends in risk, in patients with juvenile idiopathic arthritis (JIA) is incompletely understood.

Methods: We performed a register-based cohort study of patients with JIA from 2001 until 2017, identified via the Swedish Patient Register. Patients with JIA were matched to five population reference subjects.

Empowering Young People Living With Juvenile Idiopathic Arthritis to Better Communicate With Families and Care Teams: Content Analysis of Semistructured Interviews.

Background: Young people living with juvenile idiopathic arthritis (JIA) face a number of communication barriers for achieving optimal health as they transition from pediatric care into adult care. Despite growing interest in mobile or wireless technologies to support health (mHealth), it is uncertain how these engagement tools might support young people, their families, and care teams to optimize preference-based treatment strategies.

Objective: This study aims to examine how an mHealth patient support system (mPSS) might foster partnership between young people living with JIA, their families, and care teams.

A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice.

Unlabelled: Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP-induced acute liver injury (APAP-ALI) and justifies development of anti-inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N-acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP-ALI.

High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (NK) cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflammation as a prototypic alarmin.

Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.

Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord.

TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis.

Objectives: Polymyositis and dermatomyositis are characterised by muscle weakness and fatigue even in patients with normal muscle histology via unresolved pathogenic mechanisms. In this study, we investigated the mechanisms by which high mobility group box protein 1 (HMGB1) acts to accelerate muscle fatigue development.

Methods: Intact single fibres were dissociated from flexor digitorum brevis (FDB) of wild type, receptor for advanced glycation endproduct (RAGE) knockout and toll like receptor 4 (TLR4) knockout mice and cultured in the absence or presence of recombinant HMGB1.

Pro-inflammatory cytokines produced by growth plate chondrocytes may act locally to modulate longitudinal bone growth.

Introduction: Interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), both cytokines upregulated during chronic inflammation, are known to suppress bone growth. So far no role of these cytokines in modulation of normal bone growth has been established.

Methodology: Applying RT-PCR and immunohistochemistry, expression of IL-1β and TNF-α was studied in cultured fetal (E20) rat metatarsal bones.

Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis.

Introduction: High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a pro-inflammatory mediator following extracellular release. HMGB1 has been increasingly recognized as a pathogenic mediator in several inflammatory diseases. Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE).

High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts.

Introduction: In addition to its direct proinflammatory activity, extracellular high mobility group box protein 1 (HMGB1) can strongly enhance the cytokine response evoked by other proinflammatory molecules, such as lipopolysaccharide (LPS), CpG-DNA and IL-1β, through the formation of complexes. Extracellular HMGB1 is abundant in arthritic joint tissue where it is suggested to promote inflammation as intra-articular injections of HMGB1 induce synovitis in mice and HMGB1 neutralizing therapy suppresses development of experimental arthritis. The aim of this study was to determine whether HMGB1 in complex with LPS, interleukin (IL)-1α or IL-1β has enhancing effects on the production of proinflammatory mediators by rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF).

Monoclonal anti-HMGB1 (high mobility group box chromosomal protein 1) antibody protection in two experimental arthritis models.

High mobility group box chromosomal protein 1 (HMGB1) is a DNA-binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB1 promotes inflammation. Experimental studies demonstrate HMGB1 to be a pathogenic factor in many inflammatory conditions including arthritis.

High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations.

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is increasingly recognized as an important proinflammatory mediator actively secreted from monocytes and macrophages and passively released from necrotic cells. In antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), the kidneys are commonly affected vital organs, characterized by focal necrotizing and/or crescentic pauci-immune glomerulonephritis. The aim of the study was to determine whether HMGB1 serum levels are elevated in AAV with renal manifestations.

A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release.

During infection, vertebrates develop "sickness syndrome," characterized by fever, anorexia, behavioral withdrawal, acute-phase protein responses, and inflammation. These pathophysiological responses are mediated by cytokines, including TNF and IL-1, released during the innate immune response to invasion. Even in the absence of infection, qualitatively similar physiological syndromes occur following sterile injury, ischemia reperfusion, crush injury, and autoimmune-mediated tissue damage.

Protective targeting of high mobility group box chromosomal protein 1 in a spontaneous arthritis model.

Objective: High mobility group box chromosomal protein 1 (HMGB-1) is a DNA binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB-1 promotes inflammation. Clinical and experimental studies demonstrate that HMGB-1 is a pathogenic factor in chronic arthritis.

The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation.

The nuclear protein HMGB1 has previously been demonstrated to act as an alarmin and to promote inflammation upon extracellular release, yet its mode of action is still not well defined. Access to highly purified HMGB1 preparations from prokaryotic and eukaryotic sources enabled studies of activation of human PBMC or synovial fibroblast cultures in response to HMGB1 alone or after binding to cofactors. HMGB1 on its own could not induce detectable IL-6 production.

High mobility group box chromosomal protein 1 acts as a proliferation signal for activated T lymphocytes.

The nuclear protein high mobility group box chromosomal protein 1 (HMGB1) can be translocated extracellularly and plays a well-established role as a pro-inflammatory mediator during innate immune responses. Much less is known about the role of HMGB1 in adaptive immunity, since only a few studies have addressed the issue. We herein activated subsets of purified, primary human T lymphocytes with solid-phase bound anti-CD3 mAb and assessed the effects of recombinant HMGB1 protein on cell proliferation when added to the cultures.

Gait pattern in rheumatoid arthritis.

The purpose of this study was to analyse kinematic and kinetic gait changes in rheumatoid arthritis (RA) patients in comparison to healthy controls and to examine whether levels of functional disability (Health Assessment Questionnaire (HAQ)-scores) were associated with gait parameters. Using a three-dimensional motion analysis system, kinematic and kinetic gait parameters were measured in 50 RA patients and 37 healthy controls. There was a significant reduction in joint motions, joint moments and work in the RA cohort compared with healthy controls.