Insight into the Interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in IgA Vasculitis (IgAV).

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) and protocadherin 1 (PCDH1) in the pathogenesis of IgAV. Our prospective study enrolled 86 patients with IgAV and 70 controls. HMGB1, RAGE, Gd-IgA1 and PCDH1 in serum and urine were determined by the enzyme-linked immunosorbent assay (ELISA) method at the onset of the disease and after a six-month interval in patients and once in the control group. Serum concentrations of HMGB1, RAGE and PCDH1 and urinary concentrations of HMGB1, RAGE, Gd-IgA1 and PCDH1 were significantly higher in patients with IgAV than in the control group (p < 0.001). Concentrations of HMGB1 (5573 pg/mL vs. 3477 pg/mL vs. 1088 pg/mL, p < 0.001) and RAGE (309 pg/mL vs. 302.4 pg/mL vs. 201.3 pg/mL, p = 0.012) in the serum of patients remained significantly elevated when the disease onset was compared with the six-month follow-up interval, and thus could be a potential marker of disease activity. Urinary concentration of HMGB1 measured in the follow-up period was higher in patients with nephritis compared to IgAV without nephritis (270.9 (146.7-542.7) ng/mmol vs. 133.2 (85.9-318.6) ng/mmol, p = 0.049) and significantly positively correlated with the urine albumine to creatinine ratio (τ = 0.184, p < 0.05), the number of erythrocytes in urine samples (τ = 0.193, p < 0.05) and with the outcome of nephritis (τ = 0.287, p < 0.05); therefore, HMGB1 could be a potential tool for monitoring patients with IgAV who develop nephritis. Taken together, our results imply a possible interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in the development of IgAV. The identification of sensitive biomarkers in IgAV may provide disease prevention and future therapeutics.

Involvement of M1-Activated Macrophages and Perforin/Granulysin Expressing Lymphocytes in IgA Vasculitis Nephritis.

We investigated the polarisation of CD68+ macrophages and perforin and granulysin distributions in kidney lymphocyte subsets of children with IgA vasculitis nephritis (IgAVN). Pro-inflammatory macrophage (M)1 (CD68/iNOS) or regulatory M2 (CD68/arginase-1) polarisation; spatial arrangement of macrophages and lymphocytes; and perforin and granulysin distribution in CD3+ and CD56+ cells were visulaised using double-labelled immunofluorescence. In contrast to the tubules, iNOS+ cells were more abundant than the arginase-1+ cells in the glomeruli. CD68+ macrophage numbers fluctuated in the glomeruli and were mostly labelled with iNOS. CD68+/arginase-1+ cells are abundant in the tubules. CD56+ cells, enclosed by CD68+ cells, were more abundant in the glomeruli than in the tubuli, and co-expressed NKp44. The glomerular and interstitial/intratubular CD56+ cells express perforin and granulysin, respectively. The CD3+ cells did not express perforin, while a minority expressed granulysin. Innate immunity, represented by M1 macrophages and CD56+ cells rich in perforin and granulysin, plays a pivotal role in the acute phase of IgAVN.

HLA Polymorphisms and Clinical Manifestations in IgA Vasculitis.

Studies concerning the genetic background of IgA vasculitis (IgAV), a small-vessel vasculitis occurring predominantly in childhood, have confirmed that the HLA-DRB1 gene showed a strong association with disease susceptibility. The objective was to investigate human leukocyte antigen (HLA) polymorphisms among Croatian patients with IgAV and their influence on disease susceptibility and clinical heterogeneity. Thus, 130 children with IgAV and 202 unrelated healthy individuals were enrolled in the study. Genomic DNA was extracted from whole peripheral blood, and HLA-A, -B, -DRB1 and -DQB1 gene polymorphism analysis was performed. HLA-A*03 (21.4% vs. 12.38%, p = 0.0092), HLA-B*37 (2.9% vs. 0.2%, p = 0.0054) and HLA-DRB1*12 (3.1% vs. 0.7%, p = 0.0216) alleles were significantly more frequent in IgAV patients than in controls. High-resolution typing revealed significantly higher frequency of HLA-DRB1*10:01 and -DRB1*11:03 among IgAV patients with gastrointestinal manifestations of the disease in comparison to controls (p = 0.0021 and p = 0.0301, respectively), while HLA-DRB1*14:01P occurred significantly more often in the group of patients who developed nephritis during the course of the disease (17.5% vs. 4.5%, p = 0.0006). Our results demonstrated that there is an association of HLA-A*03, HLA-B*37 and HLA-DRB1*12 alleles with susceptibility to IgAV in the examined Croatian pediatric population. Studies which aim to determine the HLA profile may contribute to the elucidation of the genetic background of autoimmune diseases, including IgAV.

The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus.

The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.

Obesity as a comorbidity in children and adolescents with autoimmune rheumatic diseases.

Childhood obesity is the public health issue with alarming rates recorded throughout developed world and an important modifiable health risk for developing various chronic diseases, with childhood-onset autoimmune rheumatic diseases among them also. The aim of this article was to summarize epidemiological, pathophysiological and clinical implication of obesity on juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), juvenile dermatomyositis (JDM), IgA vasculitis (IgAV) and Kawasaki disease (KD). We reviewed PubMed database and selected 74 relevant articles. Epidemiological data of obesity among children with autoimmune rheumatic diseases indicate an increased prevalence of it. Pathophysiological link between obesity, humoral adipokines and cytokines released from fat tissue and childhood-onset autoimmune rheumatic diseases is complex and still not entirely clear. From the clinical point of view, obesity was not associated with disease activity in JIA and cSLE, but proved to contribute on functional impairment in both diseases and affect poor treatment response in JIA patients. Early atherosclerosis and cardiovascular disease (CVD) development in obese children and adolescents with JIA, cSLE and JDM are certainly important obesity-related complications. Understanding how obesity affects children and adolescents with autoimmune rheumatic diseases may encourage clinicians to consider taking better preventive strategies in this population to improve their long-term outcome.

The Association of HMGB1 and RAGE Gene Polymorphisms with IgA Vasculitis.

High-mobility group box 1 (HMGB1) is a pleiotropic cytokine that propagates inflammation by its extracellular action of interacting with the receptor for advanced glycation end products (RAGE). Both HMGB1 and RAGE play multiple roles in the pathogenesis of a variety of inflammatory and autoimmune diseases. We investigated the association of five single-nucleotide polymorphisms (SNPs) of the HMGB1 gene (rs1412125, rs2249825, rs1045411, rs1060348, rs41369348) and four SNPs of the RAGE gene (rs1800624, rs1800625, rs2070600, rs3134940) with the susceptibility and clinical features of paediatric patients with IgA vasculitis (IgAV), also known as Henoch-Schönlein's purpura. This case‒control study included 103 children with IgAV (experimental group) and 150 age-matched healthy individuals (control group). The strength of the association between different groups and alleles or genotypes of HMGB1 and RAGE was estimated using odds ratios (ORs) and 95% confidence intervals (CIs). The HMGB1 polymorphisms rs41369348, rs1045411, rs2249825 and rs1412125 were associated with the development of generalized purpuric rash, and rs1412125 was associated with IgAV nephritis (IgAVN). The RAGE polymorphism rs2070600 might be linked to the development of arthritis in IgAV patients. There was no statistically significant association between the analysed polymorphisms and susceptibility to IgAV. This is the first study to propose an association between several HMGB1 and RAGE polymorphisms and different phenotypes in the clinical course of IgAV in a paediatric population. Further research on other polymorphisms of HMGB1 and RAGE should be conducted in a larger number of patients.

Serum S100A12 levels in children with childhood-onset systemic lupus erythematosus, systemic juvenile arthritis, and systemic undefined recurrent fevers.

BACKGROUND: We compared serum levels of S100A12, a proinflammatory protein predominantly secreted by neutrophils, in children with newly diagnosed childhood-onset systemic lupus erythematosus (cSLE), systemic juvenile arthritis (sJIA), and systemic undefined recurrent fevers (SURFS) to examine its role as a diagnostic and discriminative marker of inflammation and to indirectly point out the importance of neutrophils and innate immunity in the pathogenesis of these diseases. MATERIALS AND METHODS: In a cross-sectional study, the serum levels of S100A12 protein of 68 children (19 with cSLE, 18 with sJIA, 7 with SURFS, and 24 controls) were determined by enzyme-linked immunosorbent assay and compared between groups and with clinical and laboratory findings. RESULTS: The median serum S100A12 levels were 469 ng/mL in the cSLE group, 6103 ng/mL in the sJIA group, 480 ng/mL in the SURFS group, and 44 ng/mL in the control group. Children with cSLE, sJIA, and SURFS had significantly higher serum S100A12 levels compared to the control group (p < 0.0001). sJIA patients had the highest levels of S100A12 in comparison to other patients (p < 0.0001), while there was no significant difference between children with cSLE and SURFS. CONCLUSION: Elevated serum SA100A12 levels in children with cSLE, sJIA, and SURFS may indicate intense neutrophil activation, which may play an important role in innate immunity in chronic inflammation in these diseases. Serum S100A12 levels could be used as a diagnostic marker of inflammation and be suitable for distinguishing sJIA and other disorders.

ASSOCIATION BETWEEN HIGH MOBILITY GROUP BOX 1 PROTEIN GENE (rs41369348) POLYMORPHISM AND IMMUNOGLOBULIN A VASCULITIS IN CHILDREN.

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.

2019 ACR/EULAR classification criteria and therapy in predicting organ damage accrual in patients with childhood-onset systemic lupus erythematosus: A retrospective study over the last 29 years.

OBJECTIVE: We explored damage occurrence in patients with childhood-onset SLE (cSLE) and aimed to predict the risk of organ damage occurrence in time. METHODS: The retrospective study included patients treated for cSLE at the Centre of Reference for Pediatric and Adolescent Rheumatology of the Republic Croatia over a 29-year period. RESULTS: The disease development of 97 patients (77 females) with cSLE was examined. The median (Q1, Q3) follow-up time was 6.5 (2.3, 12.0) years. SDI was determined at 5 time points (6, 12, 24, 36 months, and last follow-up). Thirty-eight patients (48%) had organ damage at the last follow-up. Prepubertal group of patients showed higher SLEDAI scores at the disease onset, while post-pubertal group had significantly lower proportion of patients with relapses. We estimated the time from the first symptom to the moment of damage and our findings suggest that it is unlikely that organ damage will occur in 50% of patients in the first 6 years since the diagnosis. The number of 2019 ACR/EULAR classification criteria at the time of diagnosis associated with SDI determined after 1 year of the follow-up period. The patients who received higher doses of glucocorticoids accumulated damage faster and mycophenolate mofetil was found to be a more frequent therapy in patients with SDI ≥3. CONCLUSION: Knowing that damage will most likely happen after the first 6 years after diagnosis in 50% of patients enables physicians to better predict damage occurrence. High number of 2019 ACR/EULAR criteria and treatment with glucocorticoids in childhood-onset SLE are associated with damage accrual and these findings could enable us to detect patients which should be closely monitored for higher risk of damage development.

Persistence and Severity of Cutaneous Manifestations in IgA Vasculitis Is Associated with Development of IgA Vasculitis Nephritis in Children.

BACKGROUND/OBJECTIVE: The purpose of this study was to evaluate the prevalence and severity of skin involvement in children with IgA vasculitis (IgAV) and its relationship with clinical and biochemical parameters and the risk of developing IgA vasculitis nephritis (IgAVN), the only cause of long-term morbidity and the main prognostic factor in IgAV patients. METHODS: This national multicenter retrospective study included 611 patients under the age of 18 years with IgAV referred to five Croatian tertiary hospitals between 2009 and 2019. Patient data were collected from a database with systematic analysis of IgAV patients in the Croatian population. RESULTS: Among the 611 children, 205 (33.55%) had purpura on the lower extremities, in 207 (33.88%) the rash extended on the trunk, in 149 (24.39%) it extended to the upper extremities, in 32 (5.24%) the rash was generalized, while 15 (2.47%) had the most severe skin symptoms: bullae, ulcerations, and necroses. IgAVN developed in 130 (21.28%) and persistent IgAVN (present for >3 months) in 48 (7.86%) children. Multivariate logistic regression found that presence of ulcerations and necroses (OR 3.20 [95% CI 1.03-9.91]), persistent purpura (OR 2.89 [95% CI 1.71-4.88]), and higher age (OR 1.16 [95% CI 1.09-1.23]) were significant predictors of IgAVN, whereas persistent purpura (OR 20.11 [95% CI 1.09-372.52]), male sex (OR 3.32 [95% CI 1.13-9.80]), and higher age (OR 1.15 [95% CI 1.00-1.30]) were predictors of persistent IgAVN. Among the laboratory parameters, higher serum urea (OR 1.43 [95% CI 1.03-2.00]) and reduction in activated partial thromboplastin time (OR 0.83 [95% CI 0.74-0.93]) were shown to have a significant impact on increasing the risk of persistent IgAVN. CONCLUSION: With increasing severity and duration of cutaneous manifestations in IgAV, the risk of developing IgAVN increases, making the prognosis worse, with a greater likelihood to need more aggressive treatment.

Geospatial clustering of childhood IgA vasculitis and IgA vasculitis-associated nephritis.

OBJECTIVES: Research on spatial variability of the incidence of IgA vasculitis (IgAV) in children and its potential implications for elucidation of the multifactorial aetiology and pathogenesis is limited. We intended to observe spatial variability of the incidence of IgAV and IgA vasculitis-associated nephritis (IgAVN) using modern geostatistical methods, and hypothesised that their spatial distribution may be spatially clustered. METHODS: Patients' data were retrospectively collected from 2009 to 2019 in five Croatian University Hospital Centres for paediatric rheumatology, and census data were used to calculate the incidence of IgAV. Using spatial empirical Bayesian smoothing, local Morans' I and local indicator of spatial autocorrelation (LISA), we performed spatial statistical analysis. RESULTS: 596 children diagnosed with IgAV were included in this study, of which 313 (52.52%) were male. The average annual incidence proportion was estimated to be 6.79 per 100 000 children, and the prevalence of IgAVN was 19.6%. Existence of spatial autocorrelation was observed in both IgAV and IgAVN; however, clustering distribution differed. While IgAV showed clustering in Mediterranean and west continental part around cities, IgAVN was clustered in the northern Mediterranean and eastern continental part, where a linear cluster following the Drava and Danube river was observed. CONCLUSION: IgAV incidence in Croatia is similar to other European countries. Spatial statistical analysis showed a non-random distribution of IgAV and IgAVN. Although aetiological associations cannot be inferred, spatial analytical techniques may help in investigating and generating new hypotheses in non-communicable diseases considering possible environmental risk factors and identification of potential genetic or epigenetic diversity.

Quality of life in children suffering from juvenile idiopathic arthritis-associated uveitis.

Uveitis (JIA-U), the most common extra-articular manifestation in juvenile idiopathic arthritis (JIA), may cause severe impairment of vision in children and affect their quality of life (QoL). Considering the lack of uveitis-related QoL assessment questionnaire, and multidimensional nature of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR), commonly used for monitoring and assessing the health status of children with JIA, we performed a cross-sectional study to investigate the potential of the JAMAR in estimation of QoL in children suffering from JIA-U. The study included 42 children with JIA, 21 of whom had JIA-U. Both children and their parents completed the JAMAR. We compared two groups of children (JIA-U and JIA without uveitis) and their parents against five extracted questionnaires items (QoL, functional ability, pain level, disease activity estimation, and current emotional state of the child) using the independent-samples t test to verify the differences and the Pearson correlation coefficient to measure the strength of a linear association between variables. No significant statistical difference in any of the examined variables was found between the two groups of children. In the groups of parents, current emotional state of children with JIA-U was assessed to be significantly worse (t = 2.05, p < 0.05) and the overall level of functioning significantly lower (t = 2.03, p < 0.05) than children without uveitis. Our results suggest the need for adding the uveitis-specific questionnaires items to JAMAR to improve its sensitivity and specificity in the assessment of QoL in children suffering from JIA-U, as well as designing a second assessment tool such as uveitis-specific questionnaires.

Serum Levels of S100A8/A9 as a Biomarker of Disease Activity in Patients with IgA Vasculitis.

S100A8/A9 protein is a well-known marker of disease activity or severity in many autoimmune and autoinflammatory diseases, but there have not been many studies about the role of S100A8/A9 in IgA vasculitis (IgAV). The aim of our study was to evaluate S100A8/A9 as a possible biomarker of activity in IgAV. We measured the serum levels of S100A8/A9 in pediatric patients with IgA vasculitis at the onset of the disease, after three months, and after six months. We compared these levels between patients with active disease, remission, and a control group, and assessed their correlation with disease activity and other markers of inflammation. Patients with active disease had significantly higher levels of serum S100A8/A9 (median ± SD) than those in the control group at the beginning of the disease (5740 ± 3157 ng/mL vs. 1447 ± 858.3 ng/mL; p < 0.0001), but also three months and six months after disease onset (p < 0.001). There was a positive correlation between S100A8/A9 serum levels and disease activity (p = 0.0003). Patients with active disease had significantly higher levels of S100A8/A9 than those in remission three months after disease onset (p = 0.0260). There was a correlation between S100A8/A9 and C-reactive protein, the C3 component of complement, ferritin, and fibrinogen. Serum levels of S100A8/A9 were also higher in patients with greater skin areas covered with rash. We demonstrated that serum levels of S100A8/A9 correlated well with disease activity and other biomarkers of inflammation in children with IgAV. According to our results, serum S100A8/A9 may be a good indicator of active disease in IgAV.

Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.

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.

Diagnostic and Management Strategies of IgA Vasculitis Nephritis/Henoch-Schönlein Purpura Nephritis in Pediatric Patients: Current Perspectives.

IgA vasculitis (IgAV) or Henoch-Schönlein purpura (HSP) is the most common vasculitis in children, and nephritis (IgAVN or HSPN) is the most important and only chronic manifestation of the disease. Despite this, there are no diagnostic criteria and we rely on the European League Against Rheumatism/Paediatric Rheumatology International Trials Organization/Paediatric Rheumatology European Society-endorsed Ankara 2008 classification criteria in our daily practice. Basic investigations that should be done in every patient with IgAVN include blood pressure measurement, estimated glomerular filtration rate and urinalysis. Kidney biopsy is still the gold standard for the diagnosis of IgAVN since noninvasive confirmation of nephritis is still pending. According to the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, the first-line treatment for with mild forms of IgAVN is oral glucocorticoids, for patients with moderate IgAVN parenterally administrated glucocorticoids in pulsed doses, while initial treatment for patients with the most severe forms of IgAVN include pulsed doses of glucocorticoids in combination with intravenous cyclophosphamide pulses. New therapeutic options are currently being tested, aiming to reduce the production of galactose-deficient IgA1 and autoantibodies or suppress the alternative or lectin complement pathway and blocking mesangial cell activation.

Cerebrovascular involvement in systemic childhood vasculitides.

Pediatric vasculitides sometimes involve central nervous system (CNS). The manifestations are diverse, ranging from headache, seizures, vertigo, ataxia, behavioral changes, neuropsychiatric symptoms, consciousness disorders, and even cerebrovascular (CV) accidents that may lead to irreversible impairment and even death. Stroke, on the other hand despite the great progress in prevention and treatment, is still one of the leading causes of morbidity and mortality in the general population. The aim of this article was to summarize CNS manifestations and CV issues observed in primary pediatric vasculitides and the current knowledge of etiology and CV risk factors, preventive strategies, and therapeutic options in this target patient population. Pathophysiological links reveal similar immunological mechanisms involved in both pediatric vasculitides and CV events with endothelial injury and damage being the central point. From the clinical point of view, CV events in pediatric vasculitides were associated with increased morbidity and poor prognosis. If damage has already occurred, the therapeutic approach consists of good management of the vasculitis itself, antiplatelet and anticoagulation therapy, and early rehabilitation. Risk factors for acquiring cerebrovascular disease (CVD) and stroke, particularly hypertension and early atherosclerotic changes, already begin in childhood, with vessel wall inflammation contributing itself, once more emphasizing that appropriate preventive measures are certainly necessary in pediatric vasculitis population to improve their long-term outcome.