Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about ...their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.
The involvement of high mobility group box-1 (HMGB1) in various inflammatory and autoimmune diseases has been documented but clinical trials on the contribution of this pro-inflammatory alarmin in ...children with juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are basically absent. To address the presence of HMGB1 and a soluble receptor for advanced glycation end products (sRAGE) in different subtypes of JIA and additionally in children with SLE, we enrolled a consecutive sample of children harvested peripheral blood as well as synovial fluids (SF) at diagnosis and correlated it with ordinary acute-phase reactants and clinical markers.
Serum and synovial fluids levels of HMGB1 and sRAGE in total of 144 children (97 with JIA, 19 with SLE and 27 healthy controls) were determined by ELISA.
The children with JIA and those with SLE were characterised by significantly higher serum levels of HMGB1 and significantly lower sRAGE levels compared to the healthy controls. A positive correlation between serum HMGB1 and ESR, CRP, α2 globulin was found while serum sRAGE levels were inversely correlated with the same inflammatory markers in children with JIA. Additionally, high level of serum HMGB1 was related to hepatosplenomegaly or serositis in systemic onset JIA.
The inverse relationship of the HMGB1 and its soluble receptor RAGE in the blood and SF indicates that inflammation triggered by alarmins may play a role in pathogenesis of JIA as well as SLE. HMGB1 may serve as an inflammatory marker and a potential target of biological therapy in these patients. Further studies need to show whether the determination of HMGB1 levels in patients with JIA can be a useful guideline for detecting disease activity.
Immunoglobulin A vasculitis (IgAV) or Henoch-Schönlein purpura is the most prevalent systemic small vessel vasculitis in childhood. High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine ...that functions as a pro-inflammatory signal, important for the activation of antigen-presenting cells and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases. The aim of this study was to investigate the role of single nucleotide polymorphism rs41369348 for HMGB1 gene in the susceptibility and clinical features of patients meeting the classification criteria for IgAV. DNA was extracted from blood cells of 76 children with IgAV and 150 age-matched healthy controls. Clinical data and laboratory parameters were collected for all IgAV patients. Although there was a higher frequency of heterozygous A/delA genotype of this gene polymorphism in IgAV group as compared with control group, no genotype difference was observed between these two groups. No statistically significant genotype differences were disclosed when patients with different IgAV clinical features were compared. In conclusion, in this study, polymorphism rs41369348 for HMGB1 was not associated with increased susceptibility to childhood IgAV, its severity or different clinical manifestations.
Biological agents are widely used in the treatment of autoimmune rheumatic disorders. We report on serious adverse events during treatment with anti-tumor necrosis factor antibody in two of our ...patients with juvenile idiopathic arthritis. One patient was treated with a biological agent due to juvenile idiopathic arthritis complicated by uveitis, developing miliary tuberculosis during treatment. After treatment with antituberculotics, she recovered completely. Her underlying disease is currently in remission. Another patient was treated for juvenile spondyloarthritis and developed an inflammatory process of the central nervous system with serious neurological deficits. He was treated with high-dose corticosteroids, followed by slowly tapering doses of corticosteroids. His neurological deficits improved, but are still present. Similar cases have been described previously, but there are no recommendations how to treat arthritis afterwards in such patients. We would like to emphasize the need of developing guidelines for further treatment of arthritis after the occurrence of serious adverse effects during treatment with biological agents. Key words: Rheumatology; Arthritis, juvenile; Tumor necrosis factor-alpha--adverse effects; Neurologic manifestations; Tuberculosis, miliary
Abstract Objective To define the clinical, radiologic and molecular characteristics of a patient with early progressive osteoarthritis and mild spondyloepiphyseal dysplasia. Methods We describe an ...18-year-old girl with early progressive osteoarthritis and mild spondyloepiphyseal dysplasia. The index case underwent a physical examination, anthropometric measurements and radiologic and laboratory studies. DNA of the patient and her only living parent (mother) was sequenced for the type II collagen gene (COL2A1). Results Mild scoliosis was noticed in the proband at the age of 13 years. At the same age, she began to have arthralgia in almost all the joints and osteoarthritis progressed fast, necessitating a hip, knee and ankle prosthesis at the age of 18 years. She was eumorphic with no ocular or hearing abnormalities. Molecular testing of the COL2A1 gene revealed a p.Gly204Val mutation. The mutation was absent in the healthy mother. Conclusion This patient provides further proof that an early osteoarthritic phenotype can be caused by a mutation in the COL2A1 gene.
Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA), caused by exaggerated but ineffective immune response. The aim of the study ...was to compare the capacity of the HLH-2004 guidelines with the capacity of the MAS guidelines from 2005, and with the new set of classification criteria from 2016 in diagnosing MAS complicating sJIA. The study included 35 children aged 1-18 diagnosed with sJIA according to ILAR criteria and treated at the Department of Pediatrics, Division of Immunology and Rheu-matology, Zagreb University Hospital Centre, in the period from 2009 to 2015. Out of 35 patients diagnosed with sJIA, there were 12 girls and 23 boys, with the mean age at disease onset (±SD) 5.51±3.65 years. Eight patients had flare of disease. With the guidelines from 2005, MAS was diag-nosed in six (17.1%) patients with sJIA. With the new set of classification criteria from 2016, MAS was diagnosed in four (11.4%) patients with sJIA. MAS was not diagnosed with the HLH-2004 guidelines. In our study, four out of six patients had MAS at the onset of sJIA, and in the rest two it occurred during relapse. Two patients with MAS developed full-blown clinical picture while another four had incomplete clinical features with minor laboratory alteration. Due to the use of different di-agnostic guidelines, we found difference in the prevalence of MAS. It was slightly higher in comparison to available studies, while other researched features, such as clinical characteristics, were similar.
The two most common entities among generally rare but under-diagnosed autoinflammatory bone disorders are chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, ...hyperostosis, and osteitis (SAPHO) syndrome. Due to their similarities, many authors consider CRMO to be a subtype of SAPHO syndrome. The aim of this study was to compare clinical, laboratory, and imaging features and outcomes of patients with CRMO and SAPHO. The analysis of the data from 6 children with CRMO (four girls and two boys, age 3.5-14 years) and of 6 children (6 boys, age 13.5-17.5 years) with SAPHO syndrome was performed. The initiating symptoms in all patients with CRMO were bone pain with multifocal bone lesions. There were no skin manifestations. Five out of six patients achieved control with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, while one patient required disease-modifying antirheumatic drugs (DMARDs). The initiating symptom in five patients with SAPHO syndrome were severe acne, while in one patient acne occurred two years after the disease onset. Two patients typically developed inflamed sternoclavicular joints and sternum, while the others showed changes affecting other skeletal regions. Three patients achieved control with NSAIDs and corticosteroids, the others required DMARDs and TNFα inhibitors. In comparison with patients with CRMO, patients with SAPHO suffered more frequent and longer lasting exacerbations. In conclusion, CRMO and SAPHO syndrome have an array of common characteristics, but also a number of differences. Nevertheless, further investigation into the etiopathogenesis is required to establish a definite relationship between CRMO and SAPHO.
The objective of this report is to explore the balance between serum and synovial fluid levels of interleukin (IL)-18 in children with juvenile idiopathic arthritis (JIA). Blood samples were obtained ...from 81 children with JIA and 18 control children. Synovial fluid samples were collected from 16 children with oligoarticular JIA. Concentrations of IL-18 were determined using commercial kit. Patients with systemic JIA had higher serum levels of IL-18 than patients with other forms of JIA or control children, both during the active (median, range: 6,240, 1,600-78,750 pg/ml) and inactive (1,615, 513-3,270 pg/ml) phase of disease analysis of variance (ANOVA), P<0.05). Levels of IL-18 in sera of children with oligoarticular JIA (255, 89-4,342 pg/ml) were similar to the respective synovial fluid levels (217, 89-1,245 pg/ml). Serum levels of IL-18 were proportional to the erythrocyte sedimentation rate and levels of C-reactive protein, but inversely proportional to the haemoglobin levels. IL-18 appears to be an important mediator of systemic JIA, while it seems of a lesser relevance in pathogenesis of other JIA forms. Therefore, inhibition of IL-18 might be a base for a successful biological therapy for systemic JIA.
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