Association of Glutathione Transferase M1, T1, P1 and A1 Gene Polymorphism and Susceptibility to IgA Vasculitis.

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.

The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C.

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.

Erythrocyte Glutathione S-Transferase Activity as a Sensitive Marker of Kidney Function Impairment in Children with IgA Vasculitis.

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.

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.

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.

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.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR Classification Criteria for Granulomatosis with Polyangiitis in Children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody-associated vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (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 pediatric 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 pediatric patients with GPA in 20 centers 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 (immunoglobulin A 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. Of patients with GPA, constitutional symptoms (85.7%) and ear-nose-throat 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.

Case report: Suspected transfusion-related acute lung injury type II in a child with refractory systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome.

Introduction: Transfusion-related acute lung injury is a rare but potentially fatal complication, which may appear during or post-transfusion of blood products. Patients with macrophage activation syndrome, a serious life-threatening complication associated with systemic juvenile idiopathic arthritis, often require transfusion or administration of blood products for correction of cytopenia, coagulopathy and hypofibrinogenemia. Case report: A 6-year-old girl with a past medical history of systemic juvenile idiopathic arthritis had the first relapse of the disease during which she developed macrophage activation syndrome. During this life-threatening complication, she received a second dose of whole blood derived filtered and irradiated platelets from a single male donor due to profound thrombocytopenia. Approximately one hour post-infusion, the patient developed progressive dyspnea, hypoxemia and bilateral pulmonary edema. She was promptly intubated and placed on mechanical ventilation for 40 h. Clinical, laboratory and radiological findings, as well as the success of supportive ventilation therapy were highly suggestive of transfusion-related acute lung injury, a life-threatening complication that occurs within six hours of blood component transfusion. Blood immunology showed no presence of anti-human neutrophil antigen and anti-leukocyte antigen class I and class II antibodies in the donor's or patient's plasma. Conclusion: To the best of our knowledge, we report the first case of a child with systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome who developed type II transfusion-related acute lung injury following platelet transfusion. It is important to consider transfusion-related acute lung injury in transfusion settings in these children and apply critical and restrictive approach for platelet transfusion.