Search

Mario Sestan, Marija Jelusic Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, CroatiaCorrespondence: Marija Jelusic, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Kispaticeva 12, Zagreb, 10 000, Croatia, Tel +385 1 23 88 701, Email marija.jelusic@mef.hrAbstract: 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.Keywords: IgA vasculitis nephritis, clinical manifestations, proteinuria, hematuria, treatment

Byline: I. Malcic (1), W.M. Novick (2), A. Dasovic-Buljevic (1), D. Jelasic (3), M. Jelusic (1), H. Kniewald (1) Keywords: Key words: Neonate -- Heart -- Juvenile xanthogranuloma -- Pediatrics Abstract: Juvenile xanthogranuloma (JXG) presents a normolipemic non-Langerhans cells histiocytosis. JXG usually presents with cutaneous lesions. Visceral involvement is rare but may affect various organs. Deep JXG differs histologically from the cutaneous form by its tendency to consist solely of homogeneous proliferation of histiocytes without any xanthomatous or Touton giant cells. Awareness of the possibility of this atypical presentation of JXG helps in making the correct histologic diagnosis, which is supported by proving adequate immunomarkers on histiocytes (mainly PG-M1, an antibody against the CD68 antigen). JXG may present with intramuscular lesions only however, rarely JXG has been reported to affect the heart but not without the typical cutaneous manifestations. We present an unusual case of deep JXG without systemic disease or metabolic abnormalities. To our knowledge, this is a first reported case of intracavitar JXG without skin lesions. Author Affiliation: (1) Department of Paediatric Cardiology and Rheumatology, Medical School Zagreb, Clinical Hospital Centre Rebro, Kispaticeva 12, 10000 Zagreb, Croatia, YU (2) Le Bonheur Children's Medical Centre, Memphis, TN USA, US (3) Department of Pathology, Medical School Zagreb, Clinical Hospital Centre Rebro, Kispaticeva 12, 10000 Zagreb, Croatia, YU

The purpose of this study was to identify new and low-frequency gene variants using whole exome sequencing (WES) in patients with childhood-onset systemic lupus erythematosus (cSLE), that may be involved in the pathogenesis of SLE. We performed WES on selected 17 trios (in some cases including other informative family members) in which the proband presented with severe, atypical clinical features, resistance to conventional therapy, a family pattern of occurrence and/or syndromic characteristics. After performing WES and analysis of gene variants, 17 novel and/or low-frequency variants were identified in 7 patients. One variant was classified as pathogenic (KMT2D, NM_003482.3:c.8626delC, predicted to truncate the protein p.(Gln2876Serfs*34)) and two as likely pathogenic according to the American College of Medical Genetics and Genomics classification guidelines (ADAR, NM_001111.3:c.2815A>G, predicted to encode p.(Ile939Val); BLK, NM_001715.2:c.211G>A, predicted to encode p.(Ala71Thr)). The other variants remain of uncertain significance at this point of time. WES is an important diagnostic and research instrument, producing a growing list of likely genes and gene variants that may be of relevance in the pathogenesis of cSLE and potentially point to novel therapeutic targets., (© 2024 The Scandinavian Foundation for Immunology.)

Objective: Granulomatosis with polyangiitis (GPA) is an ANCA-associated vasculitis. The 2022 ACR/EULAR-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in paediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA., Methods: Retrospective data of paediatric patients with GPA in 20 centres from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated., Results: The study included 77 patients with GPA and 108 controls [IgA vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1) and Cogan's syndrome (n = 1)] with a median age of 17.8 and 15.2 years, respectively. Among patients with GPA, constitutional symptoms (85.7%) and ENT involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (P = 0.229 and P = 0.733, respectively)., Conclusion: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly., (© Crown copyright 2023.)

Objective: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice., Methods: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure., Results: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS., Conclusion: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Because of the unpredictable efficacy of methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA), the possibility of a favourable outcome is reduced in more than 30% of patients. To investigate the possible influence of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) gene deletion polymorphisms on MTX efficacy in patients with JIA, we determined these polymorphisms in 63 patients with JIA who did not achieve remission and 46 patients with JIA who achieved remission during MTX therapy. No significant differences were observed in the distribution of single GSTM1 or GSTT1 deletion polymorphisms or their combination between the two groups: 58.7% to 63.5%; p = 0.567, 17.4% to 22.2%; p = 0.502, and 13% to 12.7%; p = 0.966, respectively. Our results suggest that GSTM1 and GSTT1 deletion polymorphisms do not influence the efficacy of MTX in patients with JIA. Additional studies are required to determine the possible influence of GST deletion polymorphisms on MTX efficacy in patients with JIA.

Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases ( GST ) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1 , GSTT1, GSTP1 , and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.

Objectives: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome., Study Design: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified., Results: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes., Conclusions: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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.

IgA vasculitis (IgAV) is the most common childhood vasculitis. The main cause of morbidity and mortality in children with IgAV is nephritis (IgAVN), but the risk of its development, severity, and chronicity remain unclear. Erythrocyte glutathione S-transferase (e-GST) activity has been previously detected as a sensitive marker of kidney function impairment in several diseases. We spectrophotometrically assessed and correlated e-GST activity between 55 IgAV patients without nephritis (IgAVwN), 42 IgAVN patients, and 52 healthy controls. At disease onset, e-GST activity was significantly higher in IgAVN patients (median (interquartile range)) (5.7 U/gHb (4.4-7.5)) than in IgAVwN patients (3.1 U/gHb (2.2-4.2); p < 0.001), and controls (3.1 U/gHb (1.9-4.2); p < 0.001). Therewithal, there were no differences between the IgAVwN patients and controls ( p = 0.837). e-GST activity was also significantly higher in the IgAVN patients than in the IgAVwN patients after 3 months (5.0 U/gHb (4.2-6.2) vs. 3.3 U/gHb (2.3-4.1); p < 0.001) and 6 months (4.2 U/gHb (3.2-5.8) vs. 3.3 U/gHb (2.1-4.1); p < 0.001) since the disease onset. Consistent correlations between e-GST activity and serum creatinine, estimated glomerular filtration rate (eGFR), and proteinuria levels were not detected. In conclusion, increased e-GST activity can serve as a subtle indicator of kidney function impairment in children with IgAV.

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.

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.

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., (© 2023. International League of Associations for Rheumatology (ILAR).)

Objective: IgA vasculitis (IgAV) (formerly Henoch-Schönlein Purpura, HSP) rarely causes severe skin lesions in children. The purpose of the research was to determine whether severe skin manifestations were associated with a more severe disease course., Methods: Severe cutaneous manifestations were defined as presence of hemorrhagic vesicles, bullae, ulcerations and/or necroses. Data were collected retrospectively from 12 international tertiary university medical centers., Results: A total of 64 patients with the most severe skin changes in IgAV/HSP and median (Q 1 , Q 3 ) age of 8.08 (5.08, 11.92) years at the disease onset were compared with 596 IgAV/HSP patients without these manfiestations and median (Q 1 , Q 3 ) age of 6.33 (4.50, 8.92) years. The patients with severe cutaneous manifestations were older in comparison to other patients with IgAV/HSP (p<0.001), they developed nephritis more frequently (40.6% vs. 20.6%, p = 0.001) with worse outcome of renal disease (p = 0.001). This group of patients also had higher frequencies of severe gastrointestinal complications like hematochezia, massive bleeding and/or intussusception (29.3% vs. 14.8%, p<0.001). d-dimer concentrations were significantly higher in these patients (4.60 mg/L vs. 2.72 mg/L, p = 0.003) and they had more frequent need for treatment with systemic glucocorticoids (84.4% vs. 37.2%, p<0.001) in comparison with the control group. Further multivariate analysis showed that severe cutaneous changes were associated with higher risk of developing nephritis [OR=3.1 (95%CI 1.04-9.21), p = 0.042] and severe gastrointestinal complications [OR=3.65 (95%CI 1.08-12.37), p = 0.038]., Conclusion: Patients with IgAV/HSP and severe skin manifestations had a more severe clinical course and more frequently required glucocorticoids compared to classic IgAV/HSP patients., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

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.